Nickel-Catalyzed Domino Heck-Type Reactions Using Methyl Esters as Cross-Coupling Electrophiles

Article abstract of DOI:10.1002/anie.201911372

While esters are frequently used as traditional electrophiles in substitution chemistry, their application in cross-coupling chemistry is still in its infancy. This work demonstrates that methyl esters can be used as coupling electrophiles in Ni-catalyzed Heck-type reactions through the challenging cleavage of the C(acyl)?O bond under relatively mild reaction conditions at either 80 or 100 °C. With the σ-Ni^II intermediate generated from the insertion of acyl Ni^II species into the tethered C=C bond, carbonyl-retentive products were formed by domino Heck/Suzuki–Miyaura coupling and Heck/reduction pathways when organoboron and mild hydride nucleophiles are used.

Full text of DOI:10.1002/anie.201911372

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Accepted Article
Title: Nickel-Catalyzed Domino Heck-Type Reactions using Methyl
Esters as Cross-Coupling Electrophiles
Authors: Yan-Long Zheng and Stephen G. Newman
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911372
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Nickel-Catalyzed Domino Heck-Type Reactions using Methyl
Esters as Cross-Coupling Electrophiles
Yan-Long Zheng and Stephen G. Newman*
esters contrasts the potential synthetic utility of these reactions.
In our own group, exploiting this key oxidative addition for
intermolecular coupling has been largely unsuccessful beyond
amidation. We hypothesized that the thermodynamic barrier and
reversibility of oxidative addition results in exceedingly low
concentration of the corresponding acyl-Ni intermediate, which
hinders effective intermolecular transmetallation reactions.[14]
Abstract: While esters are frequently used as traditional electrophiles
in substitution chemistry, their application in cross-coupling chemistry
is still in its infancy. In this work, we demonstrate that methyl esters
can be used as coupling electrophiles in Ni-catalyzed Heck-type
reactions via challenging cleavage of the C(acyl)-O bond under
relatively mild conditions at 80 or 100 °C. With the σ-Ni(II)
intermediate generated from the insertion of acyl Ni(II) species to the
tethered C=C bond, a series carbonyl-retentive products were formed
via domino Heck/Suzuki-Miyaura coupling and Heck/reduction
pathways when organoboron and mild hydride nucleophiles are
used.
Transition-metal-catalyzed cross-couplings are among the
most important frequently used reactions in organic synthesis.[1]
Traditionally, aryl halides and pseudohalides are use as
electrophilic coupling partners that are readily activated by low
valent Pd or Ni catalysts.[2] In recent years, significant
achievements have been made in the activation of stronger, more
robust bonds. For instance, many phenol derivatives[3] have been
shown to be viable alternatives to aryl bromides and iodides.
Similar progress has been made in the use of acyl electrophiles.[4]
Most recently, moderately activated esters and amides have been
shown to undergo a variety of coupling reactions to form carbonyl-
containing or decarbonylated products (Scheme 1A).[5] While
these acyl electrophiles are reasonably robust and capable of
participating in diverse chemistry,[6] they are seldom commercially
available and are often prepared from the corresponding
carboxylic acid or acid chloride, detracting from their synthetic
utility.
The use of abundant methyl esters is a particularly appealing
alternative to more activated surrogates. However, the absence
of coordinating and/or electron-withdrawing functionality renders
oxidative addition into the strong C(acyl)–O bond a significant
challenge. Garg, Houk and co-workers first demonstrated that
methyl esters could be activated for cross-coupling reactivity[7]
with the use of a Ni catalyst.[8] While this transformation was
limited to methyl naphthoate derivatives activated by
stoichiometric Al(OtBu)3, later reports by the Rueping,[9]
Yamaguchi,[10] and our[11] labs demonstrated that these limitations
could be overcome, albeit at temperatures from 140 to 170 °C
(Scheme 1B). DFT studies support the hypothesis that a Ni(0)
catalysts is capable of oxidatively adding to the strong C(acyl)–O
bond of a methyl ester with reasonable activation energies,[8,12]
though formation of the corresponding acyl-Ni complex is
thermodynamically uphill and likely reversible. This contrasts
more traditional oxidative addition reactions of Pd(0) and Ni(0)
with organohalides, which are usually irreversible.[13] The
relatively small number of reports on cross-coupling of methyl
Scheme 1. Esters and amides as electrophiles in the cross-coupling reactions
In 2017, the Garg[15] and Stanley[16] groups independently
reported the trapping of amide-derived acyl-Ni intermediates
intramolecularly by the insertion of a tethered allyl fragment, a
step which is generally proposed to be energetically downhill.[17]
Sequential
β-hydride
elimination
or
intermolecular
transmetallation with an orgnaoboron nucleophile forms the
corresponding Mizoroki-Heck or Suzuki-Miyaura products,
respectively (Scheme 1C). Inspired by these seminal works, we
proposed that valuable and diverse products of Ni-catalyzed ester
activation could be formed under relatively mild conditions by
exploiting an intramolecular cyclization step to trap the unstable
acyl-Ni intermediate (Scheme 1D). In contrast to the use of N-boc
amides as acyl electrophiles, methyl esters are widely available
and the corresponding methyl 2-allylbenzoate derivatives are
accessible in a single step by allylation of the corresponding
organohalide. Herein, we describe how Ni-catalyzed activation of
methyl esters can be used to form formal carboacylation and
hydroacylation products by intramolecular cyclization at much
[a]
Y.- L. Zheng, Prof. S. G. Newman*
Centre for Catalysis Research and Innovation, Department of
Chemistry and Biomolecular Sciences, University of Ottawa,
10 Marie-Curie, Ottawa, Ontario K1N 6N5, Canada.
E-mail: stephen.newman@uottawa.ca
Supporting information for this article is given via a link at the end of
the document.
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milder temperatures than have been reported in related
intermolecular couplings.
We began our investigation of the activation of methyl ortho-
allylbenzoate (1a) with catalytic Ni(cod)2. Our related amidation
reaction with IPr (bis(2,6-diisopropylphenyl)imidaze-2-ylidene) as
ligand required 140 °C to achieve appreciable conversion.[11] With
4-methoxybenzeneboronic acid (2a) as a nucleophile, an 18%
yield of indanone product 3a was observed at 90 °C with K3PO4
as the base in toluene (Table 1, entry 1). The choice of ligand was
highly important (entries 2–6), with saturated NHC ligand SIPr
being best (entry 7), giving 41% yield with the remainder of the
mass balance being isomerized 1a.[18] This side product formation
was suppressed in ethereal solvents (entries 8, 9). CsF was found
to give comparable yield to K3PO4 (entry 11), while KF was
ineffective (entry 10). Surprisingly, a mixture of these two was
ultimately found to be reproducibly superior to either component
alone, increasing the yield of 3a to 72% (entry 12).[19] Lastly,
reducing the reaction temperature to 80 °C provided 75% yield,
which could be readily isolated (entry 13).
Table 1. Optimization of the Ni-catalyzed Heck/Suzuki-Miyaura coupling of
methyl ester 1a.[a]
Entry
Ligand
IPr.HCl
Solvent
PhMe
PhMe
Base
K3PO4
K3PO4
% Yield
18
1
2
IMes.HCl
trace
3
4
ICy.HCl
PCy3
PhMe
PhMe
PhMe
PhMe
PhMe
THF
K3PO4
K3PO4
0
0
5
dcype
K3PO4
0
0
6
dppp
K3PO4
7
SIPr.HBF4
SIPr.HBF4
SIPr.HBF4
SIPr.HBF4
SIPr.HBF4
SIPr.HBF4
SIPr.HBF4
K3PO4
41
Scheme 2. Substrate scope of arylboronic acids. [a] General reaction
conditions: olefinic ester (0.20 mmol), arylboronic acid (0.5 mmol), Ni(cod)2 (10
mol%), SIPr.HBF4 (20 mol%), t-BuOK (20 mol%), CsF (0.5 mmol) and KF (0.4
mmol) in THF (0.2 M) at 80 °C for 16 h, yields for isolated products. [b] Isolated
yield on 7.4 mmol scale. [c] Yield of 3a using ethyl, n-butyl, or isopropyl ester as
starting material instead of 1a.
8
K3PO4
60
9
DME
THF
K3PO4
58
10
11
12
13[d]
KF
trace
63 (66)[b]
72
THF
CsF
With optimized conditions in hand, the reaction of methyl ortho-
allyl benzoate was studied with various boronic acid coupling
partners. Indanone 3a could be isolated in 71% yield, and other
meta (3b), and para (3b–3e) ethereal substituents including OMe,
OBu, OPh and OCF3 (3b to 3e) on the boronic acid were similarly
efficient. Arylboronic acids bearing para alkyl groups (3f and 3g),
disubstituted electron donating group (3h and 3i), meta-fluoro
group (3j), and both an electron-donating and – withdrawing
group (3k) provided yields from 56% to 74%. A strongly electron
withdrawing acetyl (3l) and ester (3m) groups were also tolerated.
Lastly, 2-naphthyl (3n) and 1-naphthyl (3o) boronic acids also
delivered the product in good yields. Lastly, the formal
carboacylation product 3a was found to be formed using ethyl,
butyl, or isopropyl-ester starting materials.
THF
CsF[b] + KF[c]
CsF[b] + KF[c]
THF
75 (71)[e]
[a] Reactions conditions: 1a: 0.2 mmol, 2a: 0.4 mmol at 0.2 M concentration.
Yield determined by 1H NMR using CH2Br2 as an internal standard. [b] CsF:
0.5 mmol, 2a: 0.5 mmol for 16 h. [c] 0.4 mmol. [d] Reaction run at 80 °C. [e]
Isolated yield.
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Scheme 4. Ni-Catalyzed Heck/Suzuki-Miyaura Coupling with Alkylborane.
Ni(cod)2 (10 mol%), SIPr.HBF4 (20 mol%), t-BuOK (20 mol%), Cs2CO3 (0.4
mmol) in THF (0.2 M) at 90 °C for 16 h, Yield determined by GC-FID.
With these optimized conditions, we started to explore the
substrate scope of this catalytic methyl ester activation/reductive
cyclization. Esters bearing methyl groups on the 4, 5 or 6 position
(8b–8d), fluorine in the 3 or 4 position (8e, 8f), and a 4,5-difluoro
substrate (8g) gave yields ranging from give 70%–82% yields.
Both strongly electron-donating methoxy (8h–8j) and strong
electron-withdrawing trifluoromethyl (8k) groups gave similarly
high yields of 76–89%, as did a naphthyl-substituted ester (8l). To
help understand the role of alcohol 9, the monodeuterated analog
d1-9 was prepared. Using this alternative reducing agent,
products 8m–o were prepared, which contained 85–89%
deuterium incorporation in the methyl group, indicating this
benzylic deuteride atom ultimately gets transferred to the product.
Beyond aiding in such mechanistic studies, deuterated molecules
have a range of applications, including use as pharmaceuticals as
tools for probing metabolic pathways.[26]
Scheme 3. Substrate scope of substituted methyl 2-allyl benzoates. [a] General
reaction conditions: olefinic ester (0.20 mmol), arylboronic acid (0.5 mmol),
Ni(cod)2 (10 mol%), SIPr.HBF4 (20 mol%), t-BuOK (20 mol%), CsF (0.5 mmol)
and KF (0.4 mmol) in THF (0.2 M) at 80 °C for 16 h, yields for isolated products.
We next focused on the evaluation of different substitution
patterns on the methyl ortho-allylbenzoate (Scheme 3). Methyl
groups on the 4, 5 or 6 position (4a–4c), fluorine in the 3, 4, or 6
position (4d–4f) and a 4, 5-difluoro substituted (4g) methyl esters
all gave the cyclization products in moderate to good yield.
Electron rich methoxy (4h, 4i) and electron poor trifluoromethyl
(4j) substituents were both well tolerated. Lastly, an ester bearing
π-extended naphthyl backbone also gave moderate reactivity,
forming 4k in 55% yield.
While exploring the potential of forming new sp3–sp3 C–C
bonds by using more challenging alkylboron nucleophiles
(Scheme 4),[20] We observed expected coupling product 7 in low
yield, along with a significant amount of reduced indanone product
8a. Given the challenges associated with preparing such products
from redox neutral hydroacylation with the corresponding
aldehyde starting materials, this reductive variant is appealing
due to the use of more robust esters as starting materials,[21] we
pursued this reductive reaction with more efficient hydride
sources.
After optimization, we identified 1-phenylethanol 9 as an
effective and environmentally benign hydride source (Scheme
5).[22] In combination with the same Ni/SIPr catalyst system and 2
equivalents of K3PO4 as the base, methyl ortho-allyl benzoate
could be cyclized to form indanone 8a in 94% isolated yield at
100 °C, along with a large amount acetophenone. In contrast, low
yields were observed with more commonly used silane[23]
formate[24] and alkoxide[25] reducing agents. Trace product was
observed in the absence of alcohol.
Scheme 5. Substrate Scope of Heck/Reduction Reaction.[a] [a] General reaction
conditions: olefinic ester (0.20 mmol), 1-phenylethanol 9 (0.4 mmol), Ni(cod)2
(10 mol%), SIPr.HCl (20 mol%), t-BuOK (20 mol%) and K3PO4 (0.4 mmol) in
toluene (0.2 M) at 100 °C for 16 h, yields for isolated products. [b] d1-9 (0.4
mmol) was used.
Based on our experimental results and previous studies on Ni-
catalyzed methyl ester activation,[8,12] plausible mechanisms for
these reactions are given in Scheme 6. The active Ni(0)–SIPr
catalyst can oxidatively add to the ester’s C(acyl)–O bond to form
acyl-Ni complex 10. Insertion to the tethered olefin provides σ-
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Ni(II) intermediate 11, which can undergo transmetallation to 12
and subsequent reductive elimination in the presence of
arylboronic acid. In the reductive cyclization, the major pathway
may involve exchange of the methoxide ligand with 1-
phenylethanol to provide intermediate 13, which is susceptible to
β-hydride elimination to 14 and subsequent reductive elimination.
The trace amounts of product formed in the absence of
exogenous alcohol and related deuterium labeling studies (see
Scheme S1 in the supporting information) suggest that 11 can
also reluctantly undergo -hydride elimination to form the product
in a minor pathway.[27] No evidence of the intramolecular Heck
enone product is observed, as is often the case in related
reactions with acyl electrophiles using Pd catalysis.[28] Ni is known
to be relatively reluctant to undergo β-hydride elimination,[17a]
which may explain this divergent behavior, as well as the need to
use 1-phenylethanol as a good hydride donor.
(NSERC), and the Canada Research Chair program. Martin
McLaughlin, Mathias Schelwies, Stephan Zuend, and Roland
Götz (BASF) are thanked for helpful discussions. The Canadian
Foundation for Innovation (CFI) and the Ontario Ministry of
Research, Innovation, & Science are thanked for essential
infrastructure.
Keywords: nickel, esters, homogeneous catalysis, Mizoroki-
Heck reactions, acylation
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Scheme 6. Proposed Mechanism
In summary, we have disclosed two new transformations that
use Ni catalysis to engage methyl esters as cross-coupling
electrophiles. In contrast to previous contributions to this field that
rely on stoichiometric Lewis acid activation, very high reaction
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relatively mild conditions. We propose that this is made possible
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electrophiles is anticipated to lead to other powerful reactions that
may prevent the need to use activated acyl species such as acid
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Acknowledgements
Financial support for this work was provided by BASF, the
National Science and Engineering Research Council of Canada
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This article is protected by copyright. All rights reserved.

10.1002/anie.201911372
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yan-Long Zheng and Stephen G.
Newman*
Page No. – Page No.
Nickel-Catalyzed Domino Heck-Type
Reactions using Methyl Esters as
Cross-Coupling Electrophiles
Methyl esters are shown to be viable cross-coupling partners in intramolecular cyclization reactions with a tethered olefin. Both
boronic acid and mild hydride donors can be used in this nickel-catalyzed reaction, providing differentially substituted indanone
products.
This article is protected by copyright. All rights reserved.