N-Acylcarbazoles and N-Acylindoles: Electronically Activated Amides for N-C(O) Cross-Coupling by Nlpto Ar Conjugation Switch

Article abstract of DOI:10.1021/acs.orglett.0c01488

The development of new amide precursors for selective, catalytic activation of carbon-nitrogen bonds in amides is a fundamental objective of this emerging reactivity manifold. We report the palladium-catalyzed Suzuki-Miyaura cross-coupling of N-acylcarbazoles and N-acylindoles with arylboronic acids by a highly selective N-C(O) cleavage. The key amide bond ground-state destabilization stems from Nlp to Ar conjugation and enables us for the first time to achieve reactivity similar to that for N-acylsulfonamide and N-acylcarbamate activation in simple anilides.

Full text of DOI:10.1021/acs.orglett.0c01488

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Letter
N‑Acylcarbazoles and N‑Acylindoles: Electronically Activated
Amides for N−C(O) Cross-Coupling by Nlp to Ar Conjugation Switch
Jonathan Buchspies,§ Md. Mahbubur Rahman,§ Roman Szostak, and Michal Szostak*
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ABSTRACT: The development of new amide precursors for selective, catalytic activation of carbon−nitrogen bonds in amides is a
fundamental objective of this emerging reactivity manifold. We report the palladium-catalyzed Suzuki−Miyaura cross-coupling of N-
acylcarbazoles and N-acylindoles with arylboronic acids by a highly selective N−C(O) cleavage. The key amide bond ground-state
destabilization stems from Nlp to Ar conjugation and enables us for the first time to achieve reactivity similar to that for N-
acylsulfonamide and N-acylcarbamate activation in simple anilides.
ctivation of amide bonds by selective oxidative insertion
Ainto the N−C(O) bond is a particularly attractive strategy
for generating acylmetals from amides.1,2 Traditionally, the
selective activation of N−C(O) amide bonds has been a major
challenge due to the classic amidic resonance (nN → π*CO
conjugation, RE, resonance energy, 15−20 kcal/mol in planar
amides) (Figure 1A,B).3 In this context, the development of
catalytic amide bond cross-couplings is of broad interest to
selectively functionalize organic molecules due to the ubiquity
of amide bonds in organic synthesis, polymers, and drug
discovery.4,5
Recently, methods for ground-state destabilization of amide
bonds in acyclic amides have been reported.6−9 The most
common is nN → π*C(O)O and nN → π*SO delocalization in
N-acylcarbamates and N-acylsulfonamides.7 Alternatively, N-
acylglutarimides8 and N-acylmonoamides9 represent twisted
tri- and diimides that rely on nN → π*C(R)O destabilization.
This activation concept leads to the twisting of amide bonds
out of planarity and enables the catalytic generation of
acylmetals by a combined steric and electronic destabiliza-
tion.10−12
have been shown to be reactive electrophiles in the oxidative
addition of N−C(O) bonds using Pd, these substrates are
unsuitable as amides for general cross-coupling reactions
because of their well-recognized hydrolytic instability triggered
by the release of the azolide ring.16−18
As a part of our ongoing research interest in amide bond
activation, we recently questioned whether Nlp to Ar
conjugation switch in N−Ar amides might be used to effect
highly selective oxidative insertion into the amide N−C(O)
bond (Figure 1C).
Herein, we report the palladium-catalyzed Suzuki−Miyaura
cross-coupling of N-acylcarbazoles and N-acylindoles with
arylboronic acids by highly selective N−C(O) bond cleavage.
The following features of our findings are noteworthy: (1)
Most importantly, this study introduces N-acylindoles and in
particular N-acylcarbazoles as highly effective amide bond
electrophiles for selective activation of the N−C(O) bond. (2)
The key amide bond ground-state destabilization stems from
Nlp to Ar conjugation in a flat carbazole ring, enabling us for
the first time to achieve reactivity similar to N-sulfonamide and
N-carbamate activation in simple anilides. (3) Mechanistic
In contrast, few methods for selective activation of
comparatively planar, electronically activated N-Ar amides
have been reported.13−15 These studies are predominantly
limited to N-methylanilides (RE = 13.5 kcal/mol),13 which
have been successfully utilized in the oxidative addition of N−
C(O) bond to Ni; however, they are generally much less
reactive than other amide precursors and unreactive using
other metals. Although N-acylpyrroles (RE = 9.3 kcal/mol)
Received: April 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01488
© XXXX American Chemical Society
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A

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Table 1. Optimization of Cross-Coupling of N-
a
Acylcarbazoles
b
entry
catalyst
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
[Pd−PEPPSI−IPr]
[Pd−PEPPSI−IPr]
[Pd−PEPPSI-IPr]
[Pd−PEPPSI−IPr]
[Pd−PEPPSI−IPr]
[Pd−PEPPSI−IPr]
[Pd−PEPPSI−IPr]
[Pd−PEPPSI−IPr]
[Pd−PEPPSI−IPr]
[Pd(IPr)(cin)Cl]
[Pd(IPr)(1-t-Bu-ind)Cl]
[Pd(IPr)(allyl)Cl]
[Pd−PEPPSI−IPent]
[Pd−PEPPSI−IMes]
Pd(OAc)2/PCy3HBF4
K2CO3
K3PO4
Na2CO3
Cs2CO3
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
THF
toluene
dioxane
DCE
THF
THF
THF
THF
THF
THF
THF
93
52
<5
17
13
89
51
28
86
92
81
71
50
15
12
c
d
a
Conditions: amide (1.0 equiv), 4-Tol-B(OH)2 (3.0 equiv), catalyst
b
(3 mol %), base (4.5 equiv), solvent (0.25 M), 80 °C, 15 h. GC/1H
NMR yields. 120 °C. Pd(OAc)2 (3 mol %), PCy3HBF4 (12 mol %),
H3BO3 (2.0 equiv), 80 °C. cin = cinnamyl; ind = indenyl; PEPPSI =
3-Cl-pyridine.
c
d
Figure 1. (a) Amide bond resonance. (b) Activation of amides and
derivatives. (c) This work: Nlp to Ar conjugation switch, N-
acylcarbazoles: new class of highly reactive amides for N−C(O)
cross-coupling.
Interestingly, the screen of various Pd(II)−NHC catalysts
indicated that catalysts bearing allyl-type throw-away ligands,
such as Pd(IPr)(cin)Cl, Pd(IPr)(1-t-Bu-ind)Cl, and Pd(IPr)-
(allyl)Cl, are also effective in this reaction, delivering the
coupling product in good to high yields (entries 10−12). In
contrast, there is a significant impact of the steric demand of
the NHC ancillary ligand, with both less sterically demanding
IMes and more hindered IPent giving low yield of the cross-
coupling product (entries 13 and 14). Finally, we also tested
the use of Pd/phosphane conditions, which resulted in low
conversion (entry 15); thus, the high σ-donation of the NHC
ligand using bench-stable, well-defined Pd(II)−NHCs is highly
beneficial for the coupling.
studies provide key insight into bond destabilization of the
amide bond. Overall, we expect that bench- and hydrolytically
stable N-acylazolides that permit facile N−C(O) activation will
provide a very attractive approach to the generation of
acylmetals from amides for a variety of coupling reactions.
In agreement with our previous studies, we hypothesized
that diminution of amidic resonance in anilides might be
rendered possible by channeling the nN → π*CO resonance
into another functional group.
After significant experimentation optimizing amide bond
geometry, we identified N-acylcarbazoles as suitable substrates
for this process. The amide bond in a model N-
benzoylcarbazole (1a) is relatively planar16c,d (τ = 25.1°; χN
= 3.2°, Winkler−Dunitz parameters, N−C(O) bond length of
1.400 Å, C = O of 1.212 Å), which can be compared with a
model predominantly planar N-methylanilide (N−C(O) bond
length of 1.355 Å, CO of 1.230 Å).13
With the optimized conditions in hand, the scope of this
transformation was examined with respect to the amide
component (Scheme 1). As shown, this amide bond activation
is well-compatible with neutral (3a), electron-donating (3b,
3c), and electron-withdrawing (3d−3g) substituents on the
amide. It is particularly noteworthy that electrophilic functional
groups that would be problematic in classical addition of hard
organometallics, such as ketones (3f) and esters (3g), are
tolerated under these catalytic conditions. Furthermore, steric
hindrance (3h), aliphatic amides (3i), and heterocyclic amides
conjugated at the deactivating, electron-rich position (3j−3k)
were easily tolerated. Next, we examined the scope of the
reaction with respect to the boronic acid component (Scheme
1). As shown, electron-neutral (3b′), electron-rich (3c′), and
electron-deficient (3d′, 3f′, 3g′) arylboronic acids were
successful substrates, albeit a lower yield using electron-
withdrawing groups has been noted (vide infra). Furthermore,
sterically hindered boronic acids (3h′), polyaromatic boronic
acids (3l, 3m), and heterocyclic boronic acids (3k′, 3n, 3o)
furnished the cross-coupling products in good to high yields.
Note that the moderate yield for the thienyl product is likely a
Selected optimization studies of the Suzuki−Miyaura cross-
coupling of N-benzoylcarbazole (1a) with 4-tolylboronic acid
are presented in Table 1. The optimized conditions utilize Pd−
PEPPSI−IPr (3 mol %), K2CO3 (4.5 equiv) in THF at 80 °C
(Table 1, entry 1, see Figure SI-1 for catalyst structures). The
use of other bases, including K3PO4, Na2CO3, Cs2CO3, and
KOH, was less successful (entries 2−5). The low yields using
Na2CO3 and Cs2CO3 are likely a balance in precatalyst
activation and acylmetal stability. Several other solvents were
examined, such as toluene, dioxane, and DCE, and provided
inferior results (entries 6−8). A higher temperature was also
compatible with this reaction, consistent with the stability of
N-acylcarbazole moiety under these conditions (entry 9).
B
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Scheme 1. [Pd−NHC]-Catalyzed Suzuki−Miyaura Cross-
Scheme 2. [Pd−NHC]-Catalyzed Suzuki−Miyaura Cross-
a
a
Coupling of N-Acylcarbazoles
Coupling of N-Acylindoles
a
Conditions: see Scheme 1.
cross-coupling of N-acylindoles, indicating the generality of the
reaction conditions.
We were further interested in testing N-acylcarbazoles as
precursors in acyl-Buchwald−Hartwig-type reactions (Scheme
3).2a We were pleased to find that a model N-benzoylcarbazole
Scheme 3. [Pd−NHC]-Catalyzed Acyl-Buchwald-Hartwig
Cross-Coupling of N-Acyl-Carbazoles
underwent smooth transamidation under Pd−NHC condi-
tions. It is expected that this class of reagents will provide an
attractive means to trigger various reactions of amides. Note
that the Suzuki−Miyaura coupling takes place under chemo-
selective conditions to transamidation of amides.2a
The synthetic advantage of N-acylcarbazoles stems from the
well-established stability of the amide bond to hydro-
lysisconditions, resulting in bench-stable, easily handled,
amide-based acyl-transfer reagents.16 Furthermore, N-acylcar-
bazoles are readily prepared from 1° amides by double N-
arylation19a or by acid-catalyzed double electrophilic cycliza-
tion using 2,5-dimethoxytetrahdyrofuran19b (Scheme 4). This
disconnection permits us to generate acylmetal intermediates
from common 1° amides. While several other strategies for
activating primary amides directly have been reported,
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (3.0 equiv), [Pd] (3
mol %), K2CO3 (4.5 equiv), THF (0.25 M), 80 °C, 15 h. See
theSupporting Information for details.
result of amide deactivation by resonance. At the present stage,
alcohols are not compatible with the reaction conditions.
Nonactivated amides are recovered unchanged. (4-
Aminophenyl)boronic acid is not tolerated. Note that the
reaction time has not been optimized.
Scheme 4. Synthesis of N-Acylcarbazoles from 1° Amides
Encouraged by the success of the Suzuki−Miyaura cross-
coupling of N-acylcarbazoles, we investigated the cross-
coupling of N-acylindoles (Scheme 2). Similar to N-
acylcarbazoles, N-acylindoles are important structural motifs
in numerous biologically active compounds and as synthetic
intermediates.16 We were pleased to find that the conditions
optimized for the cross-coupling of N-acylcarbazoles are also
suitable for the cross-coupling of N-acylindoles. As shown
using representative examples, electronic- (3a, 3c, 3f, 3b′, 3c′,
3g′) and steric variation (3h′) is well-accommodated in the
C
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including N,N-Boc2,7d N-pyrimidyl,10 and N-Ac activation,9 N-
acylcarbazoles benefit from the stability of the N−Ar linkage,
cf. other precursors.
Intrigued by the high reactivity of N-acylcarbazoles in the
cross-coupling, we conducted selectivity and kinetic studies
(Scheme 5). (1) Selectivity experiments demonstrated that N-
N−C(O) activation by Nlp to Ar conjugation. The
delocalization is much enhanced by the flat carbazole ring
(Figure 1B).
To gain insight into the energetic parameters of the amide
bond, we conducted computational studies on ground-state-
destabilization in N-acylcarbazoles (Scheme 6). As summar-
Scheme 5. Selectivity Studies
Scheme 6. Effect of Activating Group: Amides Employed in
Computational Studies and Rotational Profile
a
a
Note a gradual decrease of RE by changing N-substituents at the
nitrogen atom. RE of planar DMAc, MeCONMe2 = 18.3 kcal/mol.
See the SI.
acylcarbazoles are significantly more reactive than N-
methylanilides (Scheme 5A) and N-phenylanilides (Scheme
5B). (2) Furthermore, intermolecular competition experiments
demonstrated full selectivity for the cross-coupling of N-
acylcarbazoles vs N-phenylanilides (Scheme 5C). (3) Most
importantly, kinetic studies demonstrated comparable reac-
tivity of N-acylcarbazoles to N,N-Ph/Ts sulfonamide activation
(Scheme 5D). N-Acylcarbamates have not been used in kinetic
studies due to low stability of N-Boc linkage under the reaction
conditions. Thus, N-carbazolyl activation permits to achieve
reactivity similar to N-sulfonamide activation in simple
anilides.2−18
Furthermore, intermolecular competition experiments with
differently substituted amides and boronic acids showed that
electron-deficient amides are more reactive (4-CF3:4-MeO =
85:15) (Scheme SI-1), while electron-rich boronic acids are
more reactive (4-MeO:4-CF3 = 73:27) (Scheme SI-1),
consistent with metal insertion as the rate-limiting step.
The development of new amide bond precursors with
rationally modified amidic resonance is fundamental for the
future progress of amide bond cross-coupling.2−18 In agree-
ment with our design, N-acylcarbazoles are predisposed for
ized in Scheme 6, N-acylcarbazoles should be benchmarked
two-directionally against anilides (such as N-Me-anilide and N-
Ph-anilide)13 and N-acylazolides (such as N-acylpyrrole and N-
acylindole).14−16
(1) Thus, resonance energy determined using the COSNAR
method20 showed that resonance in 1a (RE = 7.8 kcal/
mol) is significantly lower than in 7−9 (4a: 10.5 kcal/
mol; 7: 9.3 kcal/mol; 8: 12.0 kcal/mol; 9: 13.5 kcal/
mol). Note that in this series, N-acylpyrrole is
hydrolytically unstable.16 The low RE of 1a can be
compared with N-Ts amides (8.0 kcal/mol).7c,d
(2) Rotational profiles determined by systematic rotation
along the O−C−N−C dihedral angle showed the energy
minimum at ca. 20° O−C−N−C angle for 1a (τ =
26.48°; χN = 8.41°) and 10° O−C−N−C angle for 4a (τ
= 14.38°; χN = 7.67°) in a syn O−C−N−Ar
conformation (ca. 10° O−C−N−C dihedral angle),
while the energy maximum is located at ca. 90° O−C−
N−C dihedral angle for 1a (τ = 71.97°; χN = 34.36°,
D
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Authors
5.42 kcal/mol) and 90° O−C−N−C dihedral angle for
4a (τ = 73.16°; χN = 31.90°, 8.12 kcal/mol) for 1a.
These values can be compared with the barrier of ca.
7.78 kcal/mol in N-acylpyrroles and 7.01 kcal/mol in N-
Ts amides.
Jonathan Buchspies − Department of Chemistry, Rutgers
University, Newark, New Jersey 07102, United States
Md. Mahbubur Rahman − Department of Chemistry, Rutgers
University, Newark, New Jersey 07102, United States
Roman Szostak − Department of Chemistry, Wroclaw
University, Wroclaw 50-383, Poland
(3) ΔPA, the difference between N-/O-protonation affin-
ities, indicated that 1a favors protonation at oxygen
(ΔPA = 10.7 kcal/mol), which is significantly lower than
in 7 (ΔPA = 21.4 kcal/mol; cf. 4a: 17.4 kcal/mol; 8:
14.2 kcal/mol; 9: 11.0 kcal/mol). Thus, while N-
activation of 1 by N-protonation is unlikely, PA values
are consistent with high hydrolytic stability of N-
acylcarbazoles.16 An interesting point regarding RE of
N-acylcarbazoles vs -pyrroles vs indoles might be derived
from C7−H steric interaction (indole). Studies to
further address this trend are ongoing and will be
published separately.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01488
Author Contributions
§J.B. and M.M.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Diminution of amidic resonance can be performed by both
steric and electronic factors.2−6 The high feasibility of N-
acylcarbazoles in oxidative insertion stems from Nlp to Ar
conjugation, wherein the presence of carbazole π-system and
the planarity of the ring with respect to the amide Nlp ensures
maximum delocalization switch away from the amide bond.4,6
This amide bond delocalization concept is likely to find
applications in catalytic reactions of the amide bond7−18 as well
as the design of more active amide bond analogues.2−6
In summary, we have developed the palladium-catalyzed
Suzuki−Miyaura cross-coupling of N-acylcarbazoles and N-
acylindoles with arylboronic acids by highly selective N−C(O)
bond cleavage. The reaction is performed using bench-stable
and operationally convenient Pd(II)−NHC precatalysts, and a
variety of reaction partners are compatible. This reaction
exploits N-acylindoles and especially N-acylcarbazoles as highly
effective amide bond electrophiles for selective oxidative
insertion into the N−C(O) bond. This activation concept of
amide bonds by electronic conjugation sets the stage for simple
N-Ar amides to be broadly applied in various catalytic
processes by N−C(O) bond activation. N-Acylcarbazoles are
bench-stable, easy to handle and generate acylmetals from 1°
amides. Mechanistic studies provided key insight into amide
bond ground-state-destabilization and for the first time showed
that the reactivity of N-acylcarbazoles is similar to that of N-
acylsulfonamides. Further development of amide cross-
coupling reactions and new catalytic applications will be
closely tied to the discovery of more effective amide bond
electrophiles. A full account on amide bond geometry
optimization will be forthcoming.
Rutgers University and the NSF (CAREER CHE-1650766)
are gratefully acknowledged for support. The Bruker 500 MHz
spectrometer used in this study was supported by the NSF-
MRI grant (CHE-1229030). We thank the Wroclaw Center for
Networking and Supercomputing (Grant No. WCSS159).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01488.
Experimental procedures, characterization data, Carte-
sian coordinates, and energies (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
E
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