Nickel-Catalyzed Borylation of Benzylic Ammonium Salts: Stereospecific Synthesis of Enantioenriched Benzylic Boronates

Article abstract of DOI:10.1021/acs.orglett.5b03455

We have developed a stereospecific, nickel-catalyzed cross-coupling of secondary benzylic ammonium salts and diboronate esters to deliver highly enantioenriched benzylic boronates. This reaction utilizes amine-derived electrophiles, which are readily available in high enantiopurity, and simple, inexpensive nickel catalysts. This reaction has broad scope, enabling synthesis of a variety of secondary benzylic boronates in good yields and excellent ee's.

Full text of DOI:10.1021/acs.orglett.5b03455

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Borylation of Benzylic Ammonium Salts:
Stereospecific Synthesis of Enantioenriched Benzylic Boronates
Corey H. Basch, Kelsey M. Cobb, 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
cross-coupling of secondary benzylic ammonium salts and
diboronate esters to deliver highly enantioenriched benzylic
boronates. This reaction utilizes amine-derived electrophiles,
which are readily available in high enantiopurity, and simple,
inexpensive nickel catalysts. This reaction has broad scope, enabling
synthesis of a variety of secondary benzylic boronates in good yields
and excellent ee’s.
nantioenriched secondary benzylic boronic esters are
valuable synthetic intermediates for the construction of
these methods only deliver achiral or racemic products.14−16
Miyaura borylations of alkyl electrophiles to deliver enantioen-
riched products are currently limited to allylic electrophiles.8,17
We have reported a stereospecific, nickel-catalyzed Suzuki−
Miyaura cross-coupling of benzylic ammonium triflates with
arylboronic acids.18,19 Amine-derived substrates are ideal
electrophiles for stereospecific cross-couplings, because amines
can be readily prepared in near-perfect enantiomeric excess via
a variety of methods.20 These amines can then be readily
transformed to trimethylammonium salts via a two-step
alkylation sequence, which requires only a single column
chromatography purification.21,22 In addition, amine-derived
substrates offer a functional group handle orthogonal to ethers,
and both amines and ammonium salts are stable to long-term
storage. We envisioned that a stereospecific Miyaura borylation
of these attractive amine-derived electrophiles would be
possible by changing the arylboronic acid to a diborane
coupling partner.23 Herein we report an enantiospecific, nickel-
catalyzed Miyaura borylation of secondary benzylic ammonium
salts to deliver benzylic boronate esters in high yields and ee’s.
This reaction represents the first example of a cross-coupling of
a benzylic electrophile to deliver a highly enantioenriched
borane and is one of the first examples of a stereospecific cross-
coupling of a benzylic electrophile and a heteroatomic
nucleophile.14,13 Furthermore, it offers complementary scope
to existing methods for asymmetric synthesis of benzylic
boronate esters, such as asymmetric hydroboration of styrenes.
We selected the borylation of ammonium triflate 1a for our
optimization. The amine precursor of 1a is commercially
available in >99% ee. We assume no loss in ee during its
conversion to ammonium triflate 1a. Using bis(pinacolato)-
diboron (B2pin2) under conditions similar to those optimized
for the arylation of secondary benzylic ammonium triflates,18a a
low yield of boronate 2 was observed (Table 1, entry 1).
E
complex molecules. Their C−B bonds can be converted with
enantiomeric fidelity to C−O bonds by oxidation1 or C−C
bonds by cross-couplings2 or Matteson-type homologa-
tions.1b,d,3 Due to their utility, various methods have been
developed to deliver these compounds in high enantiomeric
enrichment (Scheme 1). From alkenes, catalytic, enantiose-
Scheme 1. Asymmetric Synthesis of Secondary Benzylic
Boronates
lective hydroboration,4 β-boration of α,β-unsaturated carbon-
yls,5 diboration,6 and 1,1-arylboration7 methods have been
developed. Borylation of allylic electrophiles also delivers
enantioenriched benzylic boronates.8 Boronate starting materi-
als can also be utilized to prepare enantioenriched benzylic
boronates. Methods utilizing boronate substrates include cross-
couplings of diboranes;9 hydrogenation, hydroboration, and
conjugate additions of vinyl boronates;10 and homologation
approaches, such as Aggarwal’s asymmetric deprotonation/
borylation route.11
Conspicuously absent from the previously reported asym-
metric syntheses of secondary benzylic boronates is a Miyaura
borylation of a benzylic electrophile.12,13 This approach would
offer a powerful alternative route from readily available starting
materials. Notable methods for C−B cross-couplings of alkyl
halides, tosylates, ammonium triflates, and ethers have been
developed using copper and nickel catalysts; however, to date
Received: December 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03455
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Borylation
Scheme 2. Scope of Ammonium Triflate
temp
yield
b
ee
c
entry
[Ni]
Ni(cod)2
L
(°C)
(%)
(%)
d
e
1
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
PPh3
70
70
rt
12
78
84
86
81
80
trace
0
n.d.
95
2
3
4
5
6
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(OAc)2·4H2O
none
98
rt
99
None
rt
97
PPh3
rt
99
f
e
e
7
g
PPh3
rt
n.d.
n.d.
8
Ni(cod)2
PPh3
rt
a
Conditions: ammonium triflate 1a (>99% ee, 0.1 mmol, 1.0 equiv),
B2pin2 (1.5 equiv), [Ni] (10 mol %), ligand (L, 22 mol %), NaOMe
b
(1.5 equiv), THF (0.2 M), 24 h, unless otherwise noted. Determined
by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal
c
standard. Ee’s of the subsequent alcohol, formed via oxidation with
H2O2 and NaOMe. Determined by HPLC analysis using a chiral
a
d
e
Conditions: ammonium triflate 1 (≥95% ee, 0.30 mmol, 1.0 equiv),
B2X4 (1.5 equiv), Ni(cod)2 (10 mol %), PPh3 (22 mol %), NaOMe
(1.5 equiv), THF (0.2 M), rt, 24 h, unless otherwise noted. Isolated
stationary phase. K3PO4 replaced NaOMe. n.d. = not determined.
f
g
11 mol % PPh3. No base. 5 mol % Ni(cod)2, 11 mol % PPh3.
1
yields. Yields in parentheses determined by H NMR analysis using
1,3,5-trimethoxybenzene as internal standard. Ee’s of the subsequent
alcohol, formed via oxidation with H2O2 and NaOMe, determined by
HPLC analysis using a chiral stationary phase. Enantiospecificity (es)
However, by changing the base from K3PO4 to NaOMe, a 78%
yield and excellent stereochemical fidelity (95% ee) were
achieved (entry 2).24 By lowering the reaction temperature,
protodeboration is minimized, leading to an even higher yield
(entry 3). Investigation of the ligand showed that P(o-Tol)3 can
be replaced with PPh3 (entry 4). Phosphine-less conditions are
also successful, but provide 2 in a slightly lower yield and ee
(entry 5). In addition, air-stable Ni(OAc)2·4H2O can be used,
with only a slight reduction in yield for the model reaction
(entry 6). However, with some other substrates, Ni(OAc)2·
4H2O proved inferior to Ni(cod)2 (not shown). Control
experiments confirmed that both nickel and base are required
for this reaction (entries 7 and 8). To obtain the highest levels
of reactivity and enantiospecificity across a range of substrates,
Ni(cod)2/PPh3 was selected as the optimal catalyst system
(entry 4). Under these conditions, lower yields were obtained
when iodide or methyl sulfate replaced triflate in the
ammonium salt (30% and 72%, respectively, not shown).
Consistent with the Suzuki arylation of benzylic ammonium
triflates, this borylation proceeds with inversion of config-
uration.22 These results compare favorably with asymmetric
hydroboration of 2-vinylnaphthalene to deliver 2a; via Rh- or
Cu-catalyzed hydroboration, 2a is formed in only 85−86%
ee.4b,d
b
c
= eeprod/eesm × 100. Opposite enantiomer of 1 used. 50 °C.
of these sensitive compounds. Nonetheless, synthetically useful
yields are obtained.
In addition to the 2-naphthyl substituent, a variety of other
arenes with extended π-systems are well tolerated, including the
more sterically hindered 1-naphthyl (2b) and both methyl and
silyl ether substituted naphthyls (2c−e). Substrates with
heteroaryl groups also undergo borylation. Benzofuran 2f was
formed in 64% yield and 98% ee. Indoles can also be utilized,
providing excellent levels of stereochemical fidelity, albeit in
lower yield (2g).
With respect to the alkyl substituent (R, Scheme 2), a wide
variety of groups can be used. Linear alkyl groups are well
tolerated, including those with trifluoromethyl and acetal
functional groups (2h−j). Impressively, the borylation is also
effective with branched alkyl substituents, such as a bulky i-Pr
group (2k). Notably, asymmetric hydroboration cannot deliver
benzylic boronates with branched substituents in this position.
Dibenzylic ammonium salts (R = aryl) were unsuccessful in this
borylation; no desired product was formed.
Under the optimized conditions, a variety of benzylic
ammonium triflates successfully underwent borylation, deliver-
ing boronate products in good yields and excellent ee’s
(Scheme 2).24 In every case, the benzylic amine precursors
were prepared or purchased in high enantiopurity, highlighting
an advantage of amine-derived electrophiles. Amines that were
not commercially available were prepared via additions to
Ellman’s sulfinimines.20b−d The sulfinamide intermediates were
isolated as single diastereomers (≥95% de), as determined by
1H NMR, and we assume the subsequent ammonium triflates
are prepared in ≥95% ee.22 As shown by the comparison of
These reaction conditions are also amenable to the use of
alternative diboranes. Borylation with bis(neopentylglycolato)-
diboron (B2neop2) and bis(hexylene glycolato)diboron
(B2hex2) delivered benzylic boronates 2l and 2m in good
yields and excellent levels of stereochemical fidelity (Scheme
2). However, these benzylic boronates proved unstable to
isolation, limiting their utility to downstream reactions that do
not require purification after the Miyaura borylation.
To demonstrate the synthetic utility and robustness, we
conducted the borylation of ammonium triflate 1c, prepared in
≥95% ee, on a 1-g scale (eq 1). We employed air-stable
Ni(OAc)2·4H2O/PPh3 as the catalyst, allowing benchtop setup.
Boronate 2c was isolated in 68% yield and near-perfect
enantiopurity (99% ee). In contrast, asymmetric hydroboration
1
yields determined by H NMR analysis and isolated yields, the
purification of some of these benzylic boronates often resulted
in 10−15% loss of product due to unavoidable decomposition
B
DOI: 10.1021/acs.orglett.5b03455
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and 1q (Scheme 5). The borylation of 1e is effective, but
borylation of 1q resulted in no desired product. In this case, the
a
Scheme 5. Substituent Effects on Reactivity
resulted in only 88% ee of 2c.4b This boronate is a direct
precursor to the anti-inflammatory drug (S)-naproxen, as
shown by the Crudden group.4b
A current limitation of these conditions is that substrates
must contain an aryl substituent with an extended π-system,
such as naphthyl.25 The borylation to form p-fluorophenyl-
substituted 2n under the standard Ni(cod)2/PPh3 conditions
led to only 5% yield after 6 h. Hypothesizing that the lower
reactivity of these substrates stems from difficulty in the
oxidative addition, we investigated the use of more electron-
donating ligands. By using a catalyst generated from Ni(cod)2
and either 1,3-bis(cyclohexyl)imidazolium tetrafluoroborate
(ICy·HBF4) or PPh2Cy with KOMe as base at increased
reaction temperature, synthetically useful yields and good ee’s
of benzylic boronates 2n−p were achieved (Scheme 3).
a
Isolated yields. Yields in parentheses determined by 1H NMR analysis
using 1,3,5-trimethoxybenzene as internal standard. Ee’s of the
subsequent alcohol, formed via oxidation with H2O2 and NaOMe,
determined by HPLC analysis using a chiral stationary phase.
methoxy group may hinder attack at C1. Attack at C3 would
result in a less stable syn-allyl nickel intermediate 6 and a
complete loss of aromaticity.26
a
Scheme 3. Borylation of Non-naphthyl Substrates
In conclusion, we have developed a stereospecific, nickel-
catalyzed Miyaura borylation of secondary, benzylic ammonium
triflates to deliver benzylic boronates in good yields and
excellent ee’s. For naphthyl-substituted substrates, this reaction
utilizes a simple and inexpensive Ni(cod)2/PPh3 or Ni(OAc)2·
H2O/PPh3 catalyst. By using a more electron-rich ligand,
borylation of non-naphthyl substrates has also been accom-
plished. This reaction represents the first example of a Miyaura
borylation of a benzylic electrophile to deliver highly
enantioenriched benzylic boronates, which represent a valuable
class of intermediates for organic synthesis.
a
Conditions: ammonium triflate 1 (≥95% ee, 0.3 mmol, 1.0 equiv),
B2pin2 (1.5 equiv), Ni(cod)2 (10 mol %), PPh2Cy (22 mol %), KOMe
(1.7 equiv), THF (1.0 M), 70 °C, 24 h, unless otherwise noted.
Average isolated yields ( 3%). Yields in parentheses determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
Average ee’s ( 1%) of the subsequent alcohol, formed via oxidation
with H2O2 and NaOMe, determined by HPLC analysis using a chiral
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03455.
■
S
b
stationary phase. 0.5 mmol scale. ICy·HBF4 (12 mol %) in place of
PPh2Cy. Result of a single experiment.
Full experimental data, details on methods and starting
materials, and copies of spectral data (PDF)
This reaction likely proceeds via an oxidative addition to
generate a benzylic nickel species, which then undergoes
transmetalation and reductive elimination to deliver an
enantioenriched benzylic boronate product (Scheme 4). As is
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mpwatson@udel.edu.
Notes
Scheme 4. Proposed Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NIH (R01 GM111820) and the University of Delaware
Research Foundation Strategic Initiatives program are gratefully
acknowledged. For instrumentation support we are thankful for
NSF CHE0421224, NSF CHE1229234, NSF CHE0840401,
NIH P20 GM104316, NIH P20 GM103541, and NIH S10
RR026962.
commonly observed in stereospecific cross-couplings of
benzylic electrophiles, greater reactivity is observed for
substrates containing aryl substituents with extended π
systems.25 This observation, along with the overall inversion
of configuration, is consistent with oxidative addition occurring
in an SN2′ fashion via attack of the nickel catalyst at the ortho
carbon to generate nickel intermediates 3 and/or 4, at least
when the loss of aromaticity is not too costly. Further support
for this hypothesis is seen by comparing the borylations of 1e
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D
DOI: 10.1021/acs.orglett.5b03455
Org. Lett. XXXX, XXX, XXX−XXX