Highly Selective and Divergent Acyl and Aryl Cross-Couplings of Amides via Ir-Catalyzed C-H Borylation/N-C(O) Activation

Article abstract of DOI:10.1021/acs.orglett.0c02105

Herein, we demonstrate that amides can be readily coupled with nonactivated arenes via sequential Ir-catalyzed C-H borylation/N-C(O) activation. This methodology provides facile access to biaryl ketones and biaryls by the sterically controlled Ir-catalyzed C-H borylation and divergent acyl and decarbonylative amide N-C(O) and C-C activation. The methodology diverts the traditional acylation and arylation regioselectivity, allowing us to directly utilize readily available arenes and amides to produce valuable ketone and biaryl motifs.

Full text of DOI:10.1021/acs.orglett.0c02105

pubs.acs.org/OrgLett
Letter
Highly Selective and Divergent Acyl and Aryl Cross-Couplings of
Amides via Ir-Catalyzed C−H Borylation/N−C(O) Activation
Pengcheng Gao and Michal Szostak*
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ABSTRACT: Herein, we demonstrate that amides can be readily
coupled with nonactivated arenes via sequential Ir-catalyzed C−H
borylation/N−C(O) activation. This methodology provides facile
access to biaryl ketones and biaryls by the sterically controlled Ir-
catalyzed C−H borylation and divergent acyl and decarbonylative
amide N−C(O) and C−C activation. The methodology diverts the
traditional acylation and arylation regioselectivity, allowing us to
directly utilize readily available arenes and amides to produce
valuable ketone and biaryl motifs.
couplings by exploiting new routes to organoboron building
blocks of broad relevance to pharmaceuticals, functional
materials, and the synthesis of fine chemicals.2−5
ondirected activation of C−H bonds is among the most
Nimportant tools for transforming functional groups in
organic synthesis.1 The value of nondirected C−H function-
alizations lies in the fact that these transformations enable the
construction of complex fragments by exploiting readily
available arenes (Figure 1A).2 One of the most promising
applications of these methods is Ir-catalyzed C−H borylation,
wherein the development of sterically and ligand-controlled
C−H functionalizations enables transformative fragment
Simultaneously, recent years have witnessed the develop-
ment of powerful strategies for activation of amide N−C(O)
bonds,6 whereby the traditional amidic resonance (nN
→
π*CO delocalization)7,8 is diverted into facile oxidative
addition of the N−C(O) amide bond by ground-state
destabilization and diminution of amidic resonance.9−12 The
value of amide cross-coupling lies in the fact that amides are
among the most ubiquitous functional groups in organic
synthesis, serve as essential scaffolds in polymers, and most
importantly constitute key linkages in peptides and pro-
teins.6−8 A prominent feature of amide bond cross-coupling is
that the acyl-metal intermediate formed after metal insertion
can undergo CO extrusion, resulting in an overall N−C(O)/
C−C bond activation to afford an aryl-metal, which allows for
the direct installation of arenes by deamidative cleavage.13
Recently, we became interested in establishing the
synergistic merger of nondirected C−H activation with
amide N−C(O) cross-coupling (Figure 1B). The utilization
of readily available arenes1−5 as an abundant source of
coupling partners together with the selective breaking of
nitrogen−carbon bonds in amides6−8 hold significant promise
to define new paradigms in the transformation of functional
groups crucial to many synthetic and biological processes.14
Received: June 25, 2020
Figure 1. (A) Meta-borylation in organic synthesis. (B) Present work.
https://dx.doi.org/10.1021/acs.orglett.0c02105
© XXXX American Chemical Society
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A

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a
Scheme 1. Acylation of Arylboronate Esters with Amides by Sequential C−H/N−C(O) Activation: Amide Scope
a
Conditions: 2 (2.0 equiv), B2pin2 (0.75 equiv), [Ir(cod)(OMe)]2 (0.5 mol %), dtbpy (1 mol %), THF, 80 °C, 24 h, 1 (1.0 equiv),
b
[Pd(IPr)(cin)Cl] (3 mol %), K2CO3 (3.0 equiv), THF:H2O = 9:1 (0.20 M), 23 °C, 16 h. Cs2CO3 (3.0 equiv), 60 °C.
a
Scheme 2. Acylation of Arylboronate Esters with Amides by Sequential C−H/N−C(O) Activation: Arene Scope
a
b
c
d
e
f
g
Conditions: see Scheme 1. [Pd(IPr)(cin)Cl] (5 mol %). Cs2CO3, 60 °C. KOH, 60 °C. Cs2CO3, THF, 80 °C. Step 1: hexane. N-Ms-N-
phenylbenzamide.
Herein, we detail the successful development of highly
selective and divergent acyl and aryl cross-couplings of amides
with nonactivated arenes via C−H/N−C(O) activation. This
methodology connects the classic sterically hindered Ir-
catalyzed C−H borylation2,3 with the biorelevant manifold of
amide bond activation6−8 to provide straightforward access to
biaryl ketones and biaryls by two inert bond activation events
and diverting the traditional acylation and arylation regiose-
lectivity. The method shows excellent functional group
tolerance, chemo- and regioselectivity. We demonstrate the
synthetic utility by late-stage derivatization of pharmaceuticals
and conjugative cross-coupling of bioactive molecules. The
B
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a
Scheme 3. Arylation of Arylboronate Esters with Amides by Sequential C−H/N−C(O)/C−C Activation: Scope
a
Conditions: 2 (2.0 equiv), B2pin2 (0.6 equiv), [Ir(cod)(OMe)]2 (0.5 mol %), dtbpy (1 mol %), THF, 80 °C, 24 h, 1 (1.0 equiv), [Pd(dppb)Cl2]
b
(5 mol %), NaHCO3 (4 equiv), MeB(OH)2 (1.5 equiv), dioxane (0.125 M), H2O, 160 °C, 16 h. 2-Methyl-N-Ms-N-phenylbenzamide. See SI for
details.
synergistic merger with nonactivated arenes opens the door to
routinely utilize amides as acyl and aryl cross-coupling
electrophiles in a wide range of chemical processes.1−14
The arylation of N,N-Boc-benzamide, which is readily
prepared in a single step from benzamide,7a with 4-tol-Bpin
was selected as the starting point of our study to identify
conditions for the cross-coupling of boronic esters with amides
(Table S1, Supporting Information). Encouragingly, we found
that the broadly applicable, air- and moisture-stable [Pd(IPr)-
(cin)Cl)] (Neolyst CX31, cin = cinnamyl)15 serves as an
efficient catalyst for this coupling to give the model biaryl
ketone product in 98% yield (entry 13). Notably, this cross-
coupling with boronic esters was found to be sensitive to the
amount of water and temperature, controlling the release of
aryl boronic acid,16 with the best results obtained in THF:H2O
(9:1) at 23 °C (cf. Table S2 for arylation). The key difference
between the two Pd catalytic systems (Table S1 vs Table S2) is
that Pd−NHCs facilitate oxidative addition/reductive elimi-
nation steps due to strong σ-donation and flexible bulk,9a
respectively, while Pd−phosphine systems in the presence of
weak base favor decarbonylation due to slowing the trans-
metalation relative to the CO deinsertion step.13 Note that the
substrates are presented on schemes to reflect how the
reactions were carried out. [Pd(IPr)(cin)Cl)] is the catalyst of
choice for amide bond Suzuki cross-coupling.9a,15
in Scheme 1, the scope of the reaction with respect to amide
precursors is very broad and encompasses a wide variety of
functional groups. Electron-rich (3a, 3c, 3e, 3t), sterically
hindered (3b, 3o, 3p), and electron-deficient (3d, 3f, 3g, 3h)
groups were well-tolerated. Electrophilic functional groups,
such as ester (3f), carbonate (3j, 3p), cyano (3k), and nitro
(3l), which would be problematic with classical Weinreb
amides, gave the desired ketone products in high yields.
Furthermore, heterocyclic amides, including thiophene (3i),
pyrazine (3q), and pyridine (3r) readily underwent coupling.
Of note, the latter example (3r) represents a direct activation
of vitamin B3 (nicotinamide), while 4-hydroxybenzamide (3j)
is a common amide pharmaceutical intermediate, demonstrat-
ing potential pharmaceutical applications (vide infra). Notably,
in all cases, the meta-substituted product was formed with
exquisite selectivity, which is in sharp contrast to the
traditional acylation with arenes giving ortho products.
The scope of the arene was also extensively studied (Scheme
2). Pleasingly, we found that this C−H/N−C(O) acylation is
compatible with a broad range of 1,3-disubstitued arenes,
giving the cross-coupling products in good to excellent yields.
Acylation of challenging electron-deficient organoboranes
substituted with ester groups (3u, 3x, 3y) is well-tolerated.
Pivalates (3v), alkyl groups (3w), ethers (3z, 3aa), ketones
(3ab), heterocycles (3ac, 3ad), amides (3af), amines (3ag),
and fluorinated arenes (3ah, 3ai) afford the desired ketone
products in high yields, in all cases featuring exclusive arylation
regioselectivity. The divergent chemoselectivity for the
activated amide is noteworthy (3af). Notably, this method
could be employed for the direct derivatization of esters of
natural products and pharmaceuticals with complex architec-
ture as illustrated by the esters of fructose (3aj), menthol
With the identified conditions in hand, we explored the
scope of the sequential C−H/N−C(O) activation (Scheme 1).
The borylation was conducted with 0.75 equiv of B2pin2 in the
presence of 0.50 mol % of [Ir(cod)(OMe)]2 and 1.0 mol % of
dtbpy.2a,b Arylboronate esters were subjected to the C(O)−N
amide cross-coupling after removing volatiles and addition of
amide derivatives. 1,3-Dimethoxybenzne was used for the
borylation reaction as the model arene substrate.2a,b As shown
C
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a
Scheme 4. Coupling of Arenes with Amides by C−H/N−C(O) Activation: Complex Arenes and Amides
a
Conditions: 2 (2.0 equiv), B2pin2 (0.75 equiv), [Ir(cod)(OMe)]2 (0.5 mol %), dtbpy (1 mol %), THF, 80 °C, 24 h, 1 (1.0 equiv),
[Pd(IPr)(cin)Cl] (3 mol %), K2CO3 (3.0 equiv), THF:H2O = 9:1 (0.20 M), 23 °C, 16 h.
(3ak), trans-androsterone (3al), cholesterol (3am), as well as
adapalene (3an) and febuxostat (3ao).
complex bioactive molecules and amides under standard
conditions (3aq−3ar).1b
The applicability to various amides was explored (Figure
S1). This C−H/N−C(O) activation works with N-acyl-
glutarimides (1w), N-acyl amides (1x), N-Ts-sulfonamides
(1y), and N-Boc-carbamates (1z), which expands the scope of
the amide component to N-cyclic and N-acyclic amides.6−9
Encouraged by the success of C−H/N−C(O) acylative
coupling, we considered the possibility of developing divergent
aryl coupling by triple C−H/N−C(O)/C−C bond activation
(Scheme 3). For this type of cross-coupling, the control of the
rate of boronic acid release is critical to match with
decarbonylation of the acyl metal.13 Although the initial
results gave no or little conversion to the biaryl product, we
discovered that the use of the MeB(OH)2 additive facilitates
the organoboronate release under these conditions,16 leading
to the efficient coupling (Table S2).
We examined the generality of the C−H/N−C(O)/C−C
biaryl coupling (Scheme 3). This method is compatible with
diverse substituents on both reaction components, including
esters (4a, 4d, 4e, 4g), heterocycles (4b), electronically
deactivated substrates (4c), halides (4f), tosylates (4h),
ketones (4j), and sterically hindered substrates (4m),
delivering the biaryl products in good to high yields. Notably,
this method delivers functional handles for further derivatiza-
tion, including electrophilic groups.
Most crucially, the synthetic potential of this biaryl C−H/
N−C(O)/C−C coupling was demonstrated in the rapid late-
stage modification of esters of natural products, such as
menthol (4q), fructose (4r), and trans-androsterone (4s), thus
underscoring the synthetic potential of this activation platform.
An assessment of various amides in the biaryl coupling was
performed (Figure S2, Supporting Information). Pleasingly, N-
cyclic (1w) as well as N-acyclic amides, such as N-acyl (1x), N-
Ts-sulfonamide (1y), and N-Ms-sulfonamide (1ak), can be
utilized in this coupling protocol to deliver biaryls from arenes
and amides in good yields.
In conclusion, an expedient method for the cross-coupling of
nonactivated arenes with amides via sequential Ir-catalyzed C−
H borylation/N−C(O) activation has been developed. This
reaction provides facile access to biaryl ketones and biaryls by
exploiting regioselective C−H activation with the divergent
reactivity of the amide bond by acyl and decarbonylative
pathways. This methodology tolerates a wide variety of
functional groups, including various amides and direct
derivatization of natural products and pharmaceuticals with
intricate architectures. Based on this methodology, we
demonstrated conjugative coupling between complex bio-
molecules. This study opens the door for arene−amide
coupling in a wide variety of chemical processes.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02105.
Procedures and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Michal Szostak − Department of Chemistry, Rutgers University,
Newark, New Jersey 07102, United States; orcid.org/0000-
0002-9650-9690; Email: michal.szostak@rutgers.edu
Author
Pengcheng Gao − Department of Chemistry, Rutgers University,
Newark, New Jersey 07102, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02105
Finally, we applied our C−H/N−C(O) activation technol-
ogy to conjugative coupling of bioactive molecules (Scheme
4). Thus, the direct derivatization of complex arenes and
amides is readily accomplished to deliver conjugates between
Notes
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
Rutgers University and the NSF (CAREER CHE-1650766)
are gratefully acknowledged for support. The 500 MHz
spectrometer was supported by the NSF-MRI grant (CHE-
1229030). P.G. thanks the China Scholarship Council (No.
201606240022) for a fellowship. We thank Dr. Shicheng Shi
(Rutgers University) for preliminary studies. We thank Mr. Qi
Wang and Prof. Hao Chen (NJIT) for assistance with HRMS
measurements.
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