Stereospecific, Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Allylic Pivalates to Deliver Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.7b02063

Recognizing the importance of all-carbon, quaternary stereocenters in complex molecule synthesis, a stereospecific, nickel-catalyzed cross-coupling of allylic pivalates with arylboroxines to deliver products equipped with quaternary stereocenters and internal alkenes was developed. The enantioenriched allylic pivalate starting materials are readily prepared, and a variety of functional groups can be incorporated on both the allylic pivalate and the arylboroxine. Additional advantages include the use of a commercially available and air-stable Ni(II) salt and BISBI ligand, mild reaction conditions, and high yields and ee's. The observed stereoinversion of this reaction is consistent with an open transition state in the oxidative addition step.

Full text of DOI:10.1021/acs.orglett.7b02063

Letter
pubs.acs.org/OrgLett
Stereospecific, Nickel-Catalyzed Suzuki−Miyaura Cross-Coupling of
Allylic Pivalates To Deliver Quaternary Stereocenters
Kelsey M. Cobb, Javon M. Rabb-Lynch, Megan E. Hoerrner, Alex Manders, Qi Zhou,†
and Mary P. Watson*
Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: Recognizing the importance of all-carbon, quaternary
stereocenters in complex molecule synthesis, a stereospecific, nickel-
catalyzed cross-coupling of allylic pivalates with arylboroxines to deliver
products equipped with quaternary stereocenters and internal alkenes
was developed. The enantioenriched allylic pivalate starting materials are
readily prepared, and a variety of functional groups can be incorporated
on both the allylic pivalate and the arylboroxine. Additional advantages
include the use of a commercially available and air-stable Ni(II) salt and
BISBI ligand, mild reaction conditions, and high yields and ee’s. The observed stereoinversion of this reaction is consistent with
an open transition state in the oxidative addition step.
ll-carbon quaternary stereocenters are prevalent in natural
with quaternary stereocenters and internal alkenes (5) are more
limited, particularly for acyclic allylic electrophiles.5 In
particular, only two arylations have been reported toward this
motif, both with exceptional stereochemical fidelity (Scheme
1B). Kobayashi has developed a stereospecific addition of aryl
cuprates to allylic picolinates.6 Morken has taken an umpolung
approach with a stereospecific, palladium-catalyzed cross-
coupling of allylic boronate esters with aryl halides.7
As we considered an efficient and convenient approach to the
synthesis of quaternary stereocenters substituted with internal
alkenes, we were inspired to combine the best aspects of these
two methods in a new nickel-catalyzed reaction. We were
attracted to allylic alcohol derivatives for their ease of
preparation in highly enantioenriched form. In addition, we
sought to identify conditions that would enable catalytic use of
the metal, as well as an aryl boron species, due to their
convenience and broad functional group tolerance.8 Based on
our previous Suzuki−Miyaura cross-coupling of allylic pivalates
to set tertiary stereocenters,9 as well as our efforts with benzylic
carboxylates to set tertiary and quaternary stereocenters,10 we
envisioned that a nickel-based catalyst would enable the desired
transformation. Herein, we report a stereospecific, nickel-
catalyzed cross-coupling of allylic pivalates with arylboroxines
to deliver products equipped with quaternary stereocenters and
internal alkenes (Scheme 1C). This reaction boasts mild
reaction conditions, broad tolerance of functional groups and
heterocycles, and high yields and ee’s.
1
Aproducts and other bioactive molecules.
A powerful
approach for the synthesis of all-carbon quaternary stereo-
centers is an allylic substitution reaction.1e,2 Such a reaction not
only delivers the desired stereocenter but also includes a
versatile alkene substituent that provides multiple opportunities
for further elaboration.3 Recognizing the potential of such an
approach, many elegant enantioselective additions to allylic
electrophiles have been developed to deliver quaternary
stereocenters substituted with terminal alkenes (2, Scheme
1A).4 In contrast, methods to prepare enantioenriched products
Scheme 1. Preparation of Allylic Quaternary Stereocenters
via Allylic Substitution
We selected the cross-coupling of secondary pivalate 6a,
readily prepared in 96% ee,11 and m-methoxyphenylboroxine
for optimization. Under our previous conditions for the
formation of tertiary stereocenters,9a we observed a high
Received: July 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
yield, but poor stereochemical fidelity (entry 1). The use of a
more electron-rich phosphine ligand resulted in a moderate
increase in enantiospecificity (es, entry 2). To maximize the
convenience of this transformation, we investigated the use of
an air-stable Ni(II) salt under these conditions and found that
Ni(OTf)2 provided even higher es, albeit in diminished yield
(entry 3). Further examination of ligand revealed that use of
bisphosphine dppf led to 93% es, but only a 30% yield with
considerable decomposition of the starting material (entry 4).
We hypothesized that the wide bite angle of dppf may be
important for high es, but that the potential redox activity of the
ferrocene may also be the cause of starting material
decomposition.12 Dppb, which has a similar bite angle to
dppf but a floppier backbone, resulted in only 79% es (entry
5).13 However, the use of the more rigid BISBI resulted in high
yield and es (entry 6).14 Additional improvements in yield and
es were realized by switching to NiCl2·DME, lowering the
catalyst loading, and reducing the reaction temperature (entries
7−8). Although even higher stereochemical fidelity is achieved
at room temperature, the yield is significantly diminished (entry
9). In addition, control experiments demonstrate that nickel is
required for the cross-coupling (entries 10−11). The use of
Ni(cod)2 instead of NiCl2·DME resulted in a quantitative yield,
but lower stereochemical fidelity (entry 12). The use of aryl
boronic acid in place of arylboroxine results in lower yields with
significant hydrolysis of pivalate.15 The use of other leaving
groups led to lower stereochemical fidelity; with an acetate
leaving group, significant hydrolysis was observed.15
Scheme 2. Scope of Aryl Boroxines
a
Conditions: pivalate 6a (98% ee, 0.40 mmol, 1.0 equiv), boroxine
(1.5 equiv), NiCl2·DME (2 mol %), BISBI (2 mol %), NaOMe (3.0
equiv), MeCN (0.4 M), 50 °C, 16 h. Average isolated yields ( 9%)
and ee’s ( 2%, determined by HPLC analysis using a chiral stationary
b
phase) of duplicate reactions. es = (eeproduct)/(eestarting material). 70 °C.
Under the optimized conditions (Table 1, entry 8), a variety
of arylboroxines underwent cross-coupling (Scheme 2). Both
electron-rich (9−11, 18, 19) and electron-poor (8, 13−17) aryl
groups can be used. In general, higher stereochemical fidelity is
observed with more electron-rich arylboroxines, but a good to
excellent es was observed in every case. For arylboroxines with
limited solubility in MeCN, an elevated temperature (70 °C)
was used to ensure complete conversion. A range of functional
groups, including ethers (8, 10), anilines (9), dioxolane (11),
trifluoromethyl (13), ketones (14), esters (15), amides (16),
and nitriles (17), were well tolerated. In addition, heteroaryl
boroxines can be used in this chemistry, as shown by efficient
formation of indole 18 and benzofuran 19.
We also investigated the scope with respect to the allylic
pivalate (Scheme 3). A variety of aryl substituents (Ar1) can be
used, including those with ortho, meta, and para substitution;
the highest stereochemical fidelities are observed with electron-
poor aryl substituents (22, 23, 24). For strongly electron-rich
aryl substituents, such as p-methoxyphenyl, significant decom-
position and little desired product were observed, likely due to
the greater reactivity of the allylic pivalate. The reaction is
somewhat sensitive to changes in the alkyl substituents (R1,
R2), but good yields and high stereochemical fidelity were
observed with bulkier (iBu) or functionalized alkyl groups (28,
29, 30). Similarly to the arylboroxine, a variety of functional
groups and heterocycles are well tolerated, as shown by silyl
ethers 21 and 30, nitrile 22, and trifluoromethyl 23, pyridine
24, benzofuran 25, and epoxide 29. The absolute configuration
of product 27 was determined to be S by oxidative cleavage to
known carboxylic acid 31 and comparison to the reported
optical rotation (eq 1).7a,16 This result shows that this arylation
proceeds with stereoinversion, consistent with our other cross-
couplings in MeCN.9b
a
Table 1. Optimization
ligand
yield
b
% ee
cd
,
entry
[Ni] (mol %)
Ni(cod)2 (5)
(mol %)
t (°C)
(%)
(% es)
1
BnPPh2
(11)
70
90
54 (56)
2
3
4
5
Ni(cod)2 (5)
PCy3 (11)
70
70
70
70
70
70
95
56
30
48
87
93
64 (67)
75 (79)
89 (93)
75 (79)
90 (95)
87 (91)
e
Ni(OTf)2 (5) PCy3 (11)
Ni(OTf)2 (5) dppf (5)
Ni(OTf)2 (5) dppb (5)
Ni(OTf)2 (5) BISBI (5)
e
e
fg
6 ,
gh
,
7
8
9
NiCl2·DME
(5)
BISBI (5)
BISBI (2)
BISBI (2)
ghi
, ,
NiCl2·DME
(2)
50
rt
96
28
91 (95)
95 (99)
ghj
, ,
NiCl2·DME
(2)
10
11
12
−
−
−
70
70
50
0
−
−
BISBI (2)
0
ghik
, , ,
Ni(cod)2 (2)
BISBI (2)
>95
66 (68)
a
Conditions: pivalate 6a (96% ee, 0.10 mmol, 1.0 equiv), m-
methoxyphenylboroxine (1.0 equiv), [Ni], ligand, NaOMe (2.0
b
equiv), MeCN (0.4 M), 3 h, unless noted otherwise. Determined
by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
c
d
To probe the influence of the alkene geometry on the
stereochemical outcome, we compared the reactions of
geraniol-derived (E)-6mm to nerol-derived (Z)-6mm (Scheme
4). Arylation of (E)-6mm proceeded in high yield with
Determined by HPLC analysis using a chiral stationary phase. es =
e
(eeproduct)/(eestarting material). KOMe (2.0 equiv) in place of NaOMe.
f
g
h
i
KOMe (3.0 equiv). (ArBO)3 (1.5 equiv). NaOMe (3.0 equiv). 16
j
k
h. 24 h. 6a (97% ee).
B
DOI: 10.1021/acs.orglett.7b02063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alkenes.15 Notably, opposite absolute configuration was
observed from the arylations of (E)- vs (Z)-6m, highlighting
the importance of the alkene geometry on the stereochemical
outcome.
a
Scheme 3. Scope of Allylic Pivalates
With respect to the mechanism, we propose oxidative
addition to give a π-allyl nickel complex, transmetalation, and
reductive elimination to deliver product 8 with stabilizing
conjugation of the alkene by the phenyl group.17 This pathway
is analogous to that proposed in our allylic arylation and
borylation to deliver tertiary stereocenters.9 Formation of a π-
allyl nickel complex is also consistent with both regioisomers of
starting material delivering the same regioisomer of product.15
The oxidative addition can proceed either via a closed transition
state (TS1 or TS2, Scheme 5) or an open transition state (TS 3
Scheme 5. Rationale for Stereoinversion
a
Conditions: pivalate 6 (98% ee, 0.40 mmol, 1.0 equiv), boroxine (1.5
equiv), NiCl2·DME (2 mol %), BISBI (2 mol %), NaOMe (3.0 equiv),
MeCN (0.4 M), 50 °C, 16 h. Average isolated yields ( 5%) and ee’s
( 2%, determined by HPLC analysis using a chiral stationary phase)
b
c
of duplicate reactions. es = (eeproduct)/(eestarting material). 70 °C. Single
or TS4). In both open and closed pathways, the transition
states differ by whether Ni adds to the re or si face of the alkene,
one of which is disfavored by developing 1,3-diaxial or A1,3
interactions. Formation of (S,E)-8 as the major product
suggests that this reaction largely proceeds via open TS3, in
which nickel adds from the opposite face of the allylic system as
the pivalate leaving group and developing A1,3 interactions are
minimized. We have previously observed that MeCN can favor
such open transition states by coordinating the nickel catalyst
and blocking pivalate coordination.9b In addition, Jarvo has
proposed that bulky N-heterocyclic carbene ligands can also
disrupt coordination of the leaving group to nickel;10c
potentially, bidentate BISBI may play a similar role. Further
experiments are needed to determine if one or both of these
interactions are relevant here.
d
e
experiment. Pivalate 6 of unknown configuration. Contaminated
with 4% of SN2 product.
Scheme 4. Effect of Alkene Geometry on Stereochemical
Outcome
In summary, we have developed a stereospecific, nickel-
catalyzed Suzuki−Miyaura cross-coupling of allylic pivalates
with arylboroxines to deliver highly enantioenriched allyl arenes
with benzylic quaternary stereocenters and internal alkenes.
The enantioenriched allylic pivalates are readily prepared, and a
variety of functional groups can be incorporated on both the
allylic pivalate and the arylboroxine. Further, the catalyst system
is comprised of a commercially available and air-stable Ni(II)
salt and BISBI ligand. Efforts to expand the scope of this
transformation are ongoing in our laboratory.
excellent stererochemical fidelity. A slightly lower yield and
stereochemical fidelity were observed with (Z)-6mm. Lower
stereochemical fidelity was also observed with other (Z)-
C
DOI: 10.1021/acs.orglett.7b02063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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/acs.or-
glett.7b02063.
■
S
Experimental details and data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mpwatson@udel.edu.
ORCID
Mary P. Watson: 0000-0002-1879-5257
Present Address
†Adesis, Inc., 27 McCullough Drive, New Castle, DE 19720.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(15) See Supporting Information.
(16) (a) Shrestha, S.; Bhattarai, B. R.; Lee, K.-H.; Cho, H. Bioorg.
Med. Chem. 2007, 15, 6535. (b) García Ruano, J. L.; Martín-Castro, A.
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(17) When the phenyl substituent is replaced by an alkyl group, low
regioselectivity is observed in the arylation.
■
The NIH (R01 GM111820) is gratefully acknowledged.
J.M.R.L. thanks UD for a University Graduate Scholar
Fellowship. A.M. thanks the UD Plastino Alumni Under-
graduate Research Fellowship programs. 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 P20 GM104316, P20
GM103541, and S10 OD016267). We thank Lotus Separations,
LLC, for assistance with SFC.
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DOI: 10.1021/acs.orglett.7b02063
Org. Lett. XXXX, XXX, XXX−XXX