Nickel-Mediated Enantiospecific Silylation via Benzylic C-OMe Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.0c04316

Benzylic stereocenters are found in bioactive and drug molecules, as enantiopure benzylic alcohols have been used to build such a stereogenic center, but are limited to the construction of a C-C bond. Silylation of alkyl alcohols has the potential to build bioactive molecules and building blocks; however, the development of such a process is challenging and unknown. Herein, we describe an unprecedented AgF-assisted nickel catalysis in the enantiospecific silylation of benzylic ethers.

Full text of DOI:10.1021/acs.orglett.0c04316

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Letter
Nickel-Mediated Enantiospecific Silylation via Benzylic C−OMe Bond
Cleavage
Venkadesh Balakrishnan,† Vetrivelan Murugesan,† Bincy Chindan, and Ramesh Rasappan*
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ABSTRACT: Benzylic stereocenters are found in bioactive and
drug molecules, as enantiopure benzylic alcohols have been used to
build such a stereogenic center, but are limited to the construction
of a C−C bond. Silylation of alkyl alcohols has the potential to
build bioactive molecules and building blocks; however, the
development of such a process is challenging and unknown.
Herein, we describe an unprecedented AgF-assisted nickel catalysis
in the enantiospecific silylation of benzylic ethers.
cleavage] in cross-coupling reactions mostly rely on the
conversion of alcohols into corresponding esters10−12 or
ethers.3,13−15 Among them, methyl ethers are highly attractive
largely because of the stability, atom economy, and a
commonly encountered protecting group in organic syn-
thesis.16 The group of Shi employed MeMgBr to successfully
cross-couple benzylic methyl ethers;17 recently, Jarvo and co-
workers improved the methodology to incorporate enantio-
pure methyl ethers in cross-coupling reactions (Scheme
1a).3,11,18−23 The success of this methodology stems from
the formation of η3-benzylnickel complexes,17,24−30 which is
favored by the molecules having extended conjugation and
lower Dewar’s energy (aromaticity).31−33
ross-coupling reactions that forge C−X (X = C, B, N, O,
CSi, etc.) bonds are of central importance in synthetic
organic chemistry.1−8 The use of enantiopure benzylic alcohol
as an electrophilic coupling partner [via C(sp3)−O bond
cleavage] is highly attractive because the benzylic stereocenters
exist in numerous bioactive and drug molecules, including
Cinacalcet, Naproxen, and Methallenestril (Scheme 1).9
Methods exploiting benzylic alcohols [via C(sp3)−O bond
Scheme 1. Cross-Coupling Reactions via C−O Bond
Cleavage
Despite the success of Grignard reagents (unhindered) as a
coupling partner in C(sp3)−OMe bond cleavage, the cross-
coupling reactions of ethers remain essentially limited to C−C
bond-forming reactions. On the contrary, organosilicons (C−
Si bond) have widespread applications across various
disciplines34−36 and are versatile intermediates in organic
synthesis.37−41 Consequently, considerable effort in cross-
coupling reactions has been spent to contribute to the
synthesis of organosilanes, including silylation via C−N bond
cleavage (Scheme 1b).37−44 Recently, for the first time, we
introduced an economical Me3SiMgI (directly synthesized
from TMSI) in cross-coupling reactions [C(sp2)−OCb bond
cleavage] for the synthesis of ArSiMe3,45 a useful organosilane
for further synthetic transformations (Scheme 1b).
Received: December 31, 2020
Published: February 2, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04316
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1333−1338
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Letter
In accordance with our interest in nickel-mediated cross-
coupling reactions,45,46 we were further interested in capital-
izing on the application of Me3SiMgI in enantiospecific cross-
coupling reactions via C(sp3)−O bond cleavage. We were
optimistic that the methodology developed by Shi,17
Jarvo,11,18−21 and others10,47,48 (Scheme 1a) could be
borrowed for the use of Me3SiMgI as the coupling partner;
however, these literature protocols were not amenable to
Me3SiMgI, and traces of the cross-coupled product were
observed (Scheme 1c), highlighting the limitation of these
literature strategies. The commonly employed silylating agent
PhMe2SiBpin13,49 also failed to furnish the desired product. As
a result, we developed an AgF-assisted nickel catalysis that
results in the complete conversion of benzylic methyl ethers.
The methodology was also extended to enantiospecific
silylation.
We commenced our study with 2-(1-methoxyethyl)-
naphthalene 1a and Me3SiMgI 2a [prepared from TMSI and
Mg (stored at room temperature)]. When benzyl methyl ether
1a was subjected to the previous methods,17,18 a minimal
amount of cross-coupled product 3a was observed (Table 1,
entries 1 and 2). Subsequently, a library of nickel catalysts and
ligands were screened, and the selected entries are listed in
Table 1. Both NiBr2·glyme and NiBr2·diglyme were equally
effective, affording the cross-coupled product 3a in 21% and
22% yields, respectively, with traces (<5%) of eliminated and
reduced byproducts 5a and 5b (entries 3 and 4, respectively).
While NiCl2·diglyme afforded product 3a in 12% yield (entry
6), Ni(cod)2 completely shut down the reaction (discussed
below). The use of a bidentate phosphine ligand (dcype) had
no impact on the yield (entry 7). This led us to screen a list of
additives, and the results are listed in Table 1 (entries 8−12).
A remarkable improvement in the yield to 66% was observed
with AgF (2 equiv) being as an additive (entry 8). The other
additives, including AgBr, LiF, and CsF, affoded product 3a in
yields of only 24%, 36%, and 34%, respectively, with a
significant amount of byproducts 5a and 5b. Pleasingly, the
yield soared to 96% when the temperature was decreased to 0
°C (entry 13), possibly slowing the degradation of nickel to
black. The use of less polar Et2O or toluene had a detrimental
effect on the yield (entries 16 and 17). No reaction was
observed when NiF2 was employed in place of NiBr2·diglyme
(entry 18). Decreasing the amount of Me3SiMgI also
decreased the yield (entry 19). Employing stoichiometric
NiBr2·diglyme afforded 3a in 44% yield and 5b in 52% yield
(entry 20) with complete consumption of 1a. Further tuning of
the reaction condition revealed that the reaction could be
carried out with 0.5 equiv of AgF and 10 mol % NiBr2·
diglyme/PCy3 without a significant compromise in the yield
(entry 14).
With the optimized conditions in hand, we moved further to
expand the scope of the substrates. Methyl ethers 1 with
various α-substituents , including alkyl and aryl groups, were
well tolerated; the cyclohexyl (1b), ethyl (1c), phenyl (1d),
and benzyl (1e) derivatives afforded the corresponding cross-
coupled products in very good yields (Table 2). The 1-
naphthyl derivative afforded product 3f in 50% isolated yield,
and the use of sterically bulkier PhMe2SiMgBr and
Ph2MeSiMgBr also afforded the corresponding products 3ga
and 3gb in good yields.50 A broad range of functional groups
were well tolerated, which provides an opportunity for further
derivatization of the cross-coupled products. Aryl ethers
[C(sp2)−O] (1i, 1j, 1t, and 1ac) were intact under the
optimized condition, and the chemoselective cross-coupled
products (3i, 3j, 3t, and 3ac) were isolated in 70%, 86%, 95%,
and 85% yields, respectively. The sensitive ketal group was
stable and afforded coupled product 3n in 52% yield; partial
decomposition of 3n may be at play. Substrates bearing
fluoride (1k), CF3 (1m), TMS (1l), amine (1ab), and amide
(1u) groups were also compatible and afforded the cross-
coupled products in very good yields. Interestingly, boronic
ester 1s afforded cross-coupled product 3s in 78% yield,
although it can provide trialkyl borane with organometallic
reagents. Ketone derivative 1o also afforded coupled product
3o in 46% yield along with traces of an undesired alcohol
byproduct. Allylic ethers were subsequently investigated;51 as
expected, the reactions were efficient, affording the syntheti-
cally versatile allylsilanes 3p−u in excellent yields and E/Z
ratios.
a
Table 1. Optimization of the Reaction Conditions
additive
(equiv)
1a, 5b
b
b
entry
deviation from above
(%)
3a (%)
c
1
Ni(cod)2/rac-BINAP
NiCl2/dppf, 110 °C
NiBr2·glyme
−
−
−
97, 4
62, 20
71, 5
<5
18
21
22, 21
<5
12
20
66
24
36
34
6
96
91, 88
70
31
66
<5
62
44
d
2
3
e
4
none
−
70, 5
5
6
Ni(cod)2
NiCl2·diglyme
−
−
95, <5
82, 0
7
dcype
−
74, 5
8
9
none
none
none
none
none
0 °C
0 °C
0 °C
AgF (2.0)
AgBr (2.0)
LiF (2.0)
CsF (2.0)
MgBr2
AgF (2.0)
AgF (0.5)
AgF (0.2)
AgF (0.5)
AgF (0.5)
−
28, <5
50, 19
55, 10
57, 8
78, 14
ND, <5
<5, <5
20, 7
79, <5
38, <5
96, <5
36, <5
ND, 52
73, <5
10
11
12
13
14
15
16
17
18
19
20
f
Et2O, 0 °C
toluene, 0 °C
NiF2, 0 °C
1.0 equiv of 2a, 0 °C
1 equiv of NiBr2·PCy3, 0 °C
0 °C
AgF (0.5)
−
AgF (0.5)
Given the importance of heteroarenes in pharmaceuticals
and agrochemicals, we subjected pyridine, benzothiophene,
and thiophene derivatives to cross-coupling reactions and
obtained cross-coupled products 3w−z in good yields. It is
worth noting that the allyl ethers (1q and 1r), pyridines (1w
and 1x), and benzothiophene 1y do not require AgF, and it is
expected that substrates with varying Dewar’s resonance
energy (aromaticity)31−33,52−57 may have a profound impact
on the outcome of the reactivity. For example, the empirical
g
21
25
a
Reaction conditions: 0.20 mmol of 1a, 0.30 mmol of Me3SiMgI·
TMEDA 2a (0.35 M in toluene), 20 mol % NiBr2·diglyme, 20 mol %
b
c
PCy3, additive, and 0.15 M THF. GC yield. With 5 mol % Ni(cod)2,
d
10 mol % rac-BINAP, and toluene for 24 h. With 2 mol % NiCl2/
dppf and 2 mol % dppf for 12 h. After 20 h. isolated yield and
repeated ∼10 times throughout the project. 1a was added after the
e
f
g
addition of all other reagents.
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a
Primary methyl ether 1ag gave 91% silylated product 3ag;
however, sterically hindered tertiary methyl ether 1ah gave
only 28% of cross-coupled product 3ah. In general, most of the
heteroarenes and methoxyethyl (MOE)-protected alcohols do
not require AgF. Although few allylic substrates afforded
excellent conversion in the absence of AgF, some of them still
require AgF to improve the conversion.
Table 2. Scope of Substrates
Unfortunately, alkene 1h did not yield the cross-coupled
product. Although alkenes are known to promote nickel-
mediated cross-coupling reactions,58,59 it has been reported
that 1,5-cyclohexadiene (COD) may form an off-cycle nickel
species that is ineffective in C−O bond cleavage.60 Similarly,
we also observed the inactivity of Ni(cod)2 (Table 1, entry 5);
however, employing 0.1 equiv of COD in the standard reaction
still afforded 82% of cross-coupled product 3a. We determined
that the inactivity of Ni(cod)2 is due to the unavailability of
COD to stabilize the Ni(0) species. With 1 equiv of styrene,
the reaction was completely shut down. The formation of
volatile silylated byproducts from 1h, styrene, and COD is
responsible for the poor conversion. A gradual increase in the
amount of COD gradually decreased the yield of 3a (Scheme
2).
Scheme 2. Alkenes Inhibit the Reaction
As expected, the strategy was successfully extended to
enantiospecific silylation of enantiopure alcohols via a two-
electron pathway (instead of SET3) to afford the cross-coupled
product with inversion of stereochemistry.20 Under the
optimized condition from Table 1, we obtained silylated
product 7a with 94% es (Scheme 3). A change in the additive,
a
Scheme 3. Radical Clock Experiment
Reaction conditions: 0.2 mmol of 1a, 0.3 mmol of Me3SiMgI·
TMEDA 2a (0.35 M in toluene), NiBr2·diglyme (10 mol %), PCy3
b
(10 mol %), AgF, and THF (0.15 M). Toluene instead of THF.
c
d
With 20 mol % NiBr2·diglyme and PCy3. With 15 mol % NiBr2·
e
f
diglyme and PCy3. Toluene:THF (4:1). With 5 mol % NiBr2·
diglyme and PCy3. With 0.24 mmol of 2a. MOE (methoxyethyl)
g
h
protection instead of methyl, MgBr2 (1.0 equiv), DPEphos (20 mol
i
%), and NiBr2·diglyme (20 mol %). NMR yield.
solvent, or temperature was detrimental to the enantiospeci-
ficity. In addition, the scope of the substrates was extended,
and the results are summarized in Table 3. Most of the methyl
ethers 6 afforded very good enantiospecificity, although a few
substrates gave moderate enantiospecificity. Benzothiophene
afforded 70% es; however, the enantiopurity of the
corresponding methyl ether was only 35%.61 The absolute
stereochemistry of product 7 was identified via Fleming−
Tamao oxidation [5d (Table 3)].
We carried out a radical clock experiment with substrate 6j
to identify the loss of enantiospecificity via the formation of a
radical intermediate; however, the reaction afforded cross-
coupled product 7j in 82% isolated yield, so thus, the
homolytic cleavage of the C−OMe bond is unlikely. The
possibility of reversible oxidative addition was also examined,
and the unreacted/recovered methyl ether 6a did not lose
resonance energy for benzothiophene (π-rich) 1y is lower than
that of naphthalene (80.3 kcal/mol vs 69.8 kcal/mol), and the
π-deficient pyridines 3w and 3x have a higher normalized
resonance energy per π-electron (β = 0.058) than naphthalene
(β = 0.055). Additional coordination from pyridine’s nitrogen
may be at play; however, thiophene 3y (β = 0.032) does
require AgF. The simple phenyl derivatives 1ad−af underwent
cross-coupling reactions with moderate conversion; however,
the products were inseparable from the impurities due to the
lower boiling point and apolar nature of the products. Phenyl
derivatives 1aa−ac (benzene, β = 0.065) require a methox-
yethyl (MOE) directing group to facilitate the oxidative
addition and to deliver products 3aa−ac in very good yields.
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a,b
Ni(0) complex A to the methyl ether leads to intermediate
Ni(II) complex B. Subsequent transmetalation with Me3SiMgI
generates intermediate complex C, which delivers cross-
coupled product 3 via reductive elimination. The catalytic
role of AgF is being studied in our laboratory, it can act as an
oxidant or halide scavenger. The in situ formation of
organosilver or bimetallic (M-Ag) complexes cannot be ruled
out without further study. They could also act as a Lewis acid.
In summary, we developed nickel-mediated silylation via
C(sp3)−O bond cleavage for the first time. The methodology
is compatible with a variety of functional groups, including
ketone, acetal, amide, amine, boronic ester, and aryl ether
groups. Heteroarenes and simple arenes are also found to be
compatible. Sterically bulkier PhMe2SiMgBr and
Ph2MeSiMgBr also afforded the cross-coupled products.
Alkenes inhibit the reaction by the formation unwanted
byproducts. A radical clock experiment showed that there is no
radical intermediate present in the reaction. The methodology
was also extended to enantiospecific silylation. The identi-
fication of the role of AgF, the actual intermediates, and the
mechanistic pathway is currently being pursued in our
laboratory.
Table 3. Enantiospecific Silylation
a
With 0.2 mmol of 6, 0.3 mmol of 2a, Me3SiMgI (0.35 M in toluene),
NiBr2·diglyme (10 mol %), PCy3 (10 mol %), AgF (0.5 equiv), and
THF (0.15 M). GC yield. Toluene instead of THF. With 20 mol
ASSOCIATED CONTENT
■
b
c
d
sı
* Supporting Information
e
% NiBr2.diglyme and PCy3. Toluene:THF (4:1).
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04316.
enantiopurity (see page 67 of the Supporting Information). In
addition, employing KOEt or NaOEt in the standard reaction
did not intercept the intermediate nickel complex (Scheme 4)
Additional observations and data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Scheme 4. Mechanistic Hypothesis
Ramesh Rasappan − School of Chemistry, Indian Institute of
Science Education and Research Thiruvananthapuram,
Thiruvananthapuram, Kerala 695551, India; orcid.org/
0000-0002-3209-3315; Email: rr@iisertvm.ac.in
Authors
Venkadesh Balakrishnan − School of Chemistry, Indian
Institute of Science Education and Research
Thiruvananthapuram, Thiruvananthapuram, Kerala
695551, India
Vetrivelan Murugesan − School of Chemistry, Indian Institute
of Science Education and Research Thiruvananthapuram,
Thiruvananthapuram, Kerala 695551, India
Bincy Chindan − School of Chemistry, Indian Institute of
Science Education and Research Thiruvananthapuram,
Thiruvananthapuram, Kerala 695551, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04316
to deliver the corresponding -OEt-substituted product of 6a.
These experiments exclude the reversibility of oxidative
addition, and a double inversion might be responsible for the
loss of enantiospecificity.21
Although a detailed mechanistic study is in progress, we
propose a mechanism based on the earlier findings.45,60 Upon
mixing NiBr2 and Me3SiMgI, we expect the formation of Ni(0)
species; however, the Ni(I) species and the Ni(I)/Ni(III)
catalytic cycle cannot be ruled out without further studies. The
formed Ni(0) species may form a reversible or irreversible ate
complex with Me3SiMgI;13 a further study is in progress to
identify the nature of the resting state. Oxidative addition of
Author Contributions
†V.B. and V.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Science and Engineering Research
Board, Ramanujan Fellowship SB/S2/RJN059/2015, and
IISER-Trivandrum for financial support. V.B., V.M., and B.C.
acknowledge IISER, Trivandrum, for fellowships.
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