Decarbonylative Suzuki-Miyaura Cross-Coupling of Aroyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.0c02250

Herein, we report a catalyst system for Pd-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of aroyl chlorides with boronic acids to furnish biaryls. This strategy is suitable for a broad range of common aroyl chlorides and boronic acids. The synthetic utility is highlighted in the direct late-stage functionalization of pharmaceuticals and natural products capitalizing on the presence of carboxylic acid moiety. Extensive mechanistic and DFT studies provide key insight into the reaction mechanism and high decarbonylative cross-coupling selectivity.

Full text of DOI:10.1021/acs.orglett.0c02250

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Letter
Decarbonylative Suzuki−Miyaura Cross-Coupling of Aroyl Chlorides
Tongliang Zhou, Pei-Pei Xie, Chong-Lei Ji, Xin Hong,* and Michal Szostak*
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ABSTRACT: Herein, we report a catalyst system for Pd-catalyzed
decarbonylative Suzuki−Miyaura cross-coupling of aroyl chlorides
with boronic acids to furnish biaryls. This strategy is suitable for a
broad range of common aroyl chlorides and boronic acids. The
synthetic utility is highlighted in the direct late-stage functionaliza-
tion of pharmaceuticals and natural products capitalizing on the
presence of carboxylic acid moiety. Extensive mechanistic and DFT
studies provide key insight into the reaction mechanism and high
decarbonylative cross-coupling selectivity.
Herein, we report to the best of our knowledge the first
catalytic system for the direct decarbonylative Suzuki−Miyaura
cross-coupling of aroyl chlorides (Figure 1B). The method
employs [Pd(η3-1-t-Bu-ind)Cl]2/PPh3 or DPEPhos and
NaHCO3 as a weak base to slow down transmetalation
relative to decarbonylation.1d The utility of this method is
highlighted in the direct functionalization of pharmaceuticals
and natural products that capitalize on the presence of the
carboxylic acid moiety to introduce the biaryl motif in a
decarbonylative fashion (Figure 1C). Furthermore, we present
detailed mechanistic and DFT studies to elucidate the
mechanistic pathway and provide benchmark for the develop-
ment of future synthetic methods.
he Suzuki−Miyaura cross-coupling of aryl chlorides is
Tone of the most powerful reactions developed (Figure
1A).1,2 On the other hand, very little progress has been made
in the development of the biaryl Suzuki−Miyaura cross-
coupling of aroyl chlorides.3 To date, only one catalyst system
has been developed by Sanford and co-workers using Pd[P(o-
tol)3]2/BrettPhos;4 however, it involves a sequential decarbon-
ylative chlorination/aryl chloride cross-coupling rather than
direct decarbonylative cross-coupling. This Suzuki reaction was
successful in only two examples of electronically activated aroyl
chlorides.
In general, aroyl chlorides, R−C(O)Cl are the most
fundamental and ubiquitous carboxylic acid derivatives.3
Despite some limitations, such as stability, aroyl chlorides are
the most common acyl transfer reagents used on daily basis in
academic and industrial laboratories worldwide.5,6 In partic-
ular, nucleophilic acyl substitution using aroyl chlorides is
among the most popular synthetic methods at present;3
however, an arsenal of acyl cross-couplings of aroyl chlorides
has also been developed, permitting access to biaryl ketones.7
In contrast to these methods, the direct arylation of aroyl
chlorides remains a major challenge. Although decarbonylative
cross-couplings have been developed as a powerful reactivity
manifold, few methods involving simple aroyl chlorides have
been established.8 In this context, although aroyl chlorides are
the most fundamental carboxylic acid derivatives,3,5,6 the biaryl
Suzuki−Miyaura cross-couplingone of the most powerful
Received: July 7, 2020
Figure 1. (a) Suzuki cross-coupling of aryl chlorides. (b, c) This
study: Decarbonylative Suzuki−Miyaura cross-coupling of aroyl
chlorides.
https://dx.doi.org/10.1021/acs.orglett.0c02250
© XXXX American Chemical Society
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A

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a
Scheme 1. Scope of Decarbonylative Suzuki−Miyaura Cross-Coupling of Aroyl Chlorides
a
Conditions: acyl chloride (1.0 equiv), boronic acid (1.5 equiv), NaHCO3 (3 equiv), [(1-t-Bu-ind)PdCl]2 (7.5 mol %), 30 mol % PPh3, dioxane
b
(0.10 M), 160 °C, 15 h. Isolated yields. 20 mol % DPEPhos. See the SI for details.
a
Scheme 2. Late-Stage Functionalization of Pharmaceuticals and Natural Products
a
Conditions: carboxylic acid (1.0 equiv), SOCl2, DMF, toluene, 75 °C, 12 h, then boronic acid (1.5 equiv), NaHCO3 (3 equiv), [(1-t-Bu-
ind)PdCl]2 (7.5 mol %), 30 mol % PPh3, dioxane (0.10 M), 160 °C, 15 h. Isolated yields. See the SI for details.
B
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acid anhydrides), which we believe would be useful for the
development of future cross-coupling methods.
Scheme 3. Mechanistic Studies with Isolated Intermediates
Our studies were initiated by the examination of the cross-
coupling of benzoyl chloride with 4-methoxyphenyl boronic
acid as the nucleophile (eq 1). The key challenge in
decarbonylative cross-coupling is the reactivity of acyl- and
arylmetal intermediates in elementary organonometallic steps.
After very extensive optimization (see Tables S1−S10,
Supporting Information), we have identified a catalyst system
consisting of [Pd(η3-1-t-Bu-ind)Cl]2 as the Pd source, PPh3 or
DPEPhos as a phosphine ligand and NaHCO3 as a base. Under
the optimized conditions, the biaryl product was formed in
93% yield with >95:5 selectivity for the biaryl vs acyl coupling.
In the model cross-coupling, the same yield was observed using
preformed (η3-1-t-Bu-ind)Pd(Cl)(PPh3) and the catalyst
formed in situ from [Pd(η3-1-t-Bu-ind)Cl]2 and PPh3. To
our knowledge, this is the first example of a beneficial effect of
allyl-supported precatalysts in decarbonylative cross-coupling,
a finding which may lead to the development of more effective
Pd(II) precatalysts in this catalysis platform.15−17
Scheme 4. Summary of Mechanistic Studiesa
It is further interesting to note that a comprehensive
optimization of η3-allyl throw-away ligands,15 such as η3-allyl,
η3-cin, η3-ind, and η3-1-t-Bu-ind in [Pd(η3-allyl)Cl]2 catalysts
across various boronic acids, was conducted and confirmed the
beneficial effect of η3-1-t-Bu-ind in all cases examined (see the
SI).
With the optimized conditions in hand, the scope and
limitations of this Suzuki−Miyaura cross-coupling were
investigated (Scheme 1). As shown, the scope of the reaction
is very broad using unbiased electrophile and accommodates a
significant electronic and steric variation. As such, electron-rich
(3a,3b) and electron-deficient (3c−3h) boronic acids are well-
tolerated. It is noteworthy that the reaction readily
accommodates electrophilic groups, such as ketones (3c),
esters (3d), chlorides (3g), and aldehydes (3h). In particular,
the tolerance to aryl chloride (3g) highlights the orthogonal
nature of decarbonylative cross-coupling vs the conventional
aryl chloride cross-coupling. Furthermore, steric hindrance
(3i−3j) and a variety of other substrates (3k−3t), including
heterocycles (3r−3t), are readily accommodated by this
decarbonylative cross-coupling. Importantly, the scope with
respect to the aroyl chloride component is similarly broad
(3u−3ak), including electrophilic substrates such as chloride
(3z), ester (3ab) or cyano (3ah−3aj). Several additional
points and limitations should be noted.18 At this stage, mono-
ortho-substitution on acyl chlorides is tolerated, while diortho-
substituted aroyl chlorides are not suitable substrates. The 4-
nitro substituent on the boronic acid allows for the cross-
coupling (4-nitro-1,1′-biphenyl, 42% yield). The ratio of 3/4 =
81:19 is consistent with the electron-withdrawing effect of the
nitro group. The 4-nitro group on aroyl chloride is tolerated
(4-methoxy-4′-nitro-1,1′-biphenyl, 31% yield, 3:4 > 95:5). It
should also be noted that aroyl chlorides are potential
lachrymators (LC50 inhalation, rat, 1.45 mg/L) and have
several other hazards.18d
synthetic transformations within the field of chemistry1,2
using aroyl chlorides as electrophiles remains a challenging
goal.
Within our program on decarbonylative cross-coupling
reactions,9 we questioned whether decarbonylative Suzuki−
Miyaura cross-coupling of aroyl chlorides might be accom-
plished using versatile Pd catalysis.10−14 Notable features of
our study include (1) the first example of a direct
decarbonylative Suzuki−Miyaura cross-coupling of aroyl
chlorides. Aroyl chlorides represent a fundamental functional
group in organic synthesis. The reaction involves a
fundamental elementary step, oxidative addition of an acyl−
Cl bond (cf. acyl−OCOR bond).9f (2) a new catalytic system
for decarbonylative cross-coupling of aroyl electrophiles (cf.
C
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Figure 2. DFT-computed free-energy-profile of Pd/PPh3-catalyzed decarbonylative biaryl Suzuki−Miyaura coupling of benzoyl chloride. See the SI
for details. .
The synthetic utility is highlighted in the direct late-stage
functionalization of pharmaceuticals and natural products that
feature carboxylic acid moiety that is readily converted in situ
to aroyl chlorides using thionyl chloridea classic sequence in
nucleophilic acyl additions3,5,6,14 (Scheme 2). The synthesis of
biaryls from probenecid (3al, antihyperuricemic), bexarotene
(3am, antineoplastic), methone (3an, monoterpene), and
cholesterol (3ao, steroid) illustrates the capacity of this
coupling in the synthesis of biaryls with a range of potential
applications.19
To study the mechanism, we conducted stoichiometric
experiments with isolated intermediates (Scheme 3 and SI).
(A) To gain insight into the facility of decarbonylation, we
prepared acyl-palladium complex 6 and subjected this complex
to the cross-coupling (Scheme 3A). Decarbonylation of 6
occurs at 80 °C, while full conversion is achieved at 160 °C
after 30 min. Furthermore, we have independently prepared
aryl-Pd complex 7 (Scheme 3A).20 The reverse reaction of 7 to
give 6 occurs under atmospheric pressure of CO within 2 h at
rt. These findings confirm that decarbonylation of acyl-
palladium 6 can occur under mild conditions at 80 °C.21
Decarbonylation of 6 is observed at temperatures as low as 60
°C (see SI).
(B) Stoichiometric experiments using benzoyl chloride in
the presence of palladium precursor and phosphine ligand
using [Pd] (1 equiv) (Pd(dba)2 or [Pd(η3-1-t-Bu-ind)Cl]2)
and PPh3 (2 equiv) give aryl-Pd complex 7 exclusively
(Scheme 3B), consistent with fast decarbonylation of
acylpalladium 6.21
(C) Experiments with acyl-Pd complex 6 in the presence of
boronic acid and base under different conditions show that at
rt only ketone 4a resulting from acyl coupling was formed,
however, at higher temperatures only biaryl 3a was observed,
even after short reaction times, reaching full conversion at 160
°C after 15 min (Scheme 3C).
(D) Stoichiometric experiments with 7 in the presence of
boronic acid and base show full conversion of aryl-palladium 7
to biaryl 3a after 15 min at 160 °C (Scheme 3D).
(E, F) Further experiments probing the effect of CO
(Scheme 3E) and the potential of acyl-palladium complex 6 as
a catalyst (Scheme 3F) demonstrate that acyl coupling is more
facile than aryl coupling and that 6 is catalytically active,
consistent with 6 as a catalytic intermediate in the cross-
coupling. Scheme 4 presents a summary of stoichiometric
studies. The results suggest that decarbonylation precedes
transmetalation. Decarbonylation is facile and occurs at
temperatures as low as 80 °C. The results indicate trans-
metalation as the rate-limiting step.
To gain further insight into the mechanism of this novel
cross-coupling, we have performed extensive computational
studies to delineate the origin of high reactivity and the
energies of elementary steps. The DFT-computed free energy
profile of Pd/PPh3-catalyzed decarbonylative biaryl Suzuki−
Miyaura cross-coupling with benzoyl chloride is shown in
Figure 2. From the substrate-coordinated complex 8, the
oxidative addition of benzoyl chloride through TS9 is very
facile, generating the acyl-palladium intermediate 10. Com-
pound 10 dissociates one of the phosphine coordinates to
allow the subsequent decarbonylation via TS12, and the
ligand−CO exchange leads to the bisligated aryl-palladium
species 14. From 14, the base-promoted transmetalation
occurs via an outer-sphere mechanism (TS16) to generate
the biaryl-palladium intermediate 17. The alternative base-free,
bicarbonate-facilitated, or inner-sphere transmetalation pro-
cesses were found less favorable (Figure S1). Compound 17
undergoes a facile aryl−aryl reductive elimination through
TS18 to produce the produce-coordinated complex 19.
D
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Subsequent product liberation regenerates the palladium
catalyst and completes the catalytic cycle. We want to
emphasize that the isolated chloride anion is a simplification
of its form in the catalytic system, complexation with cationic
species could further stabilize the dissociated chloride anion
and make the product liberation more exergonic. Based on the
DFT-computed free energy profile, the rate-determining step
of the catalytic cycle is the transmetalation step via TS16. This
step requires an overall barrier of 29.9 kcal/mol compared with
the on-cycle resting state acyl-palladium intermediate 10.
An additional point is the speciation of Pd catalyst at 160
°C. Decarbonylation of 6 to 7 occurs at 60 °C (1 h, 13%) and
the entire reaction at 100 °C (3a, 21%). Therefore, we can
make a reasonable assumption of catalyst speciation between
25 and 80 °C and apply it to our reaction conditions.
Moreover, considering the boiling point of 1,4-dioxane, the
system temperature should be close to 120 °C in the
stoichiometric transformation. Furthermore, we have made
attempts to determine the fate of the Pd in stoichiometric
reactions of 7. Preliminary studies indicate the formation of
Pd(PPh3)2 in the cross-coupling of 7 (0.5 h, 17%).
In summary, we have identified a new catalyst system for the
decarbonylative Suzuki−Miyaura cross-coupling of aroyl
chlorides. Synthetically, aroyl chlorides are the most
fundamental carboxylic acid derivatives. This report demon-
strates that aroyl chlorides could be successfully utilized in the
powerful Suzuki−Miyaura biaryl cross-coupling manifold. The
synthetic utility has been highlighted in the direct function-
alization of pharmaceuticals and natural products capitalizing
on the presence of carboxylic acid moiety. Mechanistic and
DFT studies have provided insight into the high reaction
selectivity and established facile decarbonylation, and decar-
bonylation preceding transmetalation. Our future studies will
be focused on expanding the scope of coupling partners in this
process.
https://pubs.acs.org/10.1021/acs.orglett.0c02250
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CAREER CHE-1650766, M.S.), the NIH
(1R35GM133326, M.S.), Rutgers University (M.S.), NSFC
(21702182 and 21873081, X.H.), Fundamental Research
Funds for the Central Universities (X.H.), and Zhejiang
University (X.H.) for generous financial support. Calculations
were performed on the high-performance computing system at
the Department of Chemistry, Zhejiang University.
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AUTHOR INFORMATION
Corresponding Authors
■
Xin Hong − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China; Email: hxchem@zju.edu.cn
Michal Szostak − Department of Chemistry, Rutgers University,
Newark, New Jersey 07102, United States; orcid.org/0000-
0002-9650-9690; Email: michal.szostak@rutgers.edu
Authors
Tongliang Zhou − Department of Chemistry, Rutgers
University, Newark, New Jersey 07102, United States;
orcid.org/0000-0002-7334-7078
Pei-Pei Xie − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Chong-Lei Ji − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Complete contact information is available at:
E
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