Suzuki-Miyaura Cross-Coupling of N-Acylpyrroles and Pyrazoles: Planar, Electronically Activated Amides in Catalytic N-C Cleavage

Article abstract of DOI:10.1021/acs.orglett.7b01575

The formation of C-C bonds from amides by catalytic activation of the amide bond has been thus far possible by steric distortion. Herein, we report the first example of a general Pd-catalyzed Suzuki-Miyaura cross-coupling of planar amides enabled by the combination of (i) electronic-activation of the amide nitrogen in N-acylpyrroles and pyrazoles and (ii) the use of a versatile Pd-NHC catalysis platform. The origin and selectivity of forming acylmetals, including the role of twist, are discussed.

Full text of DOI:10.1021/acs.orglett.7b01575

Letter
pubs.acs.org/OrgLett
Suzuki−Miyaura Cross-Coupling of N‑Acylpyrroles and Pyrazoles:
Planar, Electronically Activated Amides in Catalytic N−C Cleavage
Guangrong Meng,† Roman Szostak,‡ and Michal Szostak*,†
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
‡Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
S
* Supporting Information
ABSTRACT: The formation of C−C bonds from amides by catalytic
activation of the amide bond has been thus far possible by steric
distortion. Herein, we report the first example of a general Pd-
catalyzed Suzuki−Miyaura cross-coupling of planar amides enabled by
the combination of (i) electronic-activation of the amide nitrogen in
N-acylpyrroles and pyrazoles and (ii) the use of a versatile Pd-NHC
catalysis platform. The origin and selectivity of forming acylmetals,
including the role of twist, are discussed.
he development of efficient methods for coupling of amides
Tby transition-metal-catalyzed N−C bond cleavage has
become an important goal in organic synthesis.1,2 With this
bond forming manifold, typically considered inert amide bonds
can be harnessed into generic acyl-metal reactivity pathways.3
Given that amides represent ubiquitous synthons in biologically
active compounds and common intermediates in organic
synthesis,4 the discovery of new catalytic reactivity by amide
N−Ccleavageundoubtedlyholdsasignificantpotentialinvarious
fields of chemistry.5,6
While methods that induce N−C bond activation7 in sterically
distorted amides8 have now been well-established,9 catalytic
processes that enable C−C bond formation from planar amides
are absent (Figure 1A). Recently, Maiti and co-workers reported
an excellent method for Ni-catalyzed step-down reduction of
amides to aromatic hydrocarbons using N-acylpyrazoles as the
reaction partners (Figure 1B).10 In the extensive mechanistic
Figure 1. (a) Metal-catalyzed activation of amides and derivatives. (b)
studies, it was elegantly shown that N−Ni-coordination at the 2-
position of the pyrazole ring is critical for high reactivity;
unfortunately, synthetically valuable N-acylpyrroles11 were found
unreactive in this process. The method constitutes a rare example
of activating planar amide bonds in Ni catalysis.12
Ni-catalyzed reduction of N-acylpyrazoles. (c) Coupling of N-
acylpyrroles and pyrazoles.
Herein, we report a Pd-catalyzed activation of N−C amide
bonds in planar amides enabled by electronic activation of the
amide N atom (Figure 1C). Cross-coupling of planar amides is
significantly more challenging than that of distorted amides as
distortion disrupts amidic resonance more effectively than
electronic destabilization.1b The following features of our study
arenoteworthy: (1) wedemonstrate thehigh reactivity ofboth N-
acylpyrroles and N-acylpyrazoles, resulting in an operationally
simple, catalytic synthesisofbiarylketonesfromN-acylpyrroles as
Weinreb amide equivalents, without resorting to a two-step
protocol via tetrahedral intermediates (Figure 2).11 (2) Since N-
acylpyrroles can be readily prepared from primary benzamides
(the Paal−Knorr pyrrole synthesis),13 our method offers a rapid
entry to metal-catalyzed coupling of unactivated primary amides.
Figure 2. Previous state-of-the-art: ketone synthesis from N-acylpyrroles
using organolithiums or Grignard reagents.11
(3) We demonstrate the beneficial effect of Pd-NHC (NHC = N-
heterocyclic carbene) catalysis14 over Pd-phosphines in the
activation of inert amide N−C bonds,9r,t which may have
implications for the design and optimization of amide cross-
coupling manifolds. (4) Mechanistic studies provide insight into
the origin and selectivity of forming acylmetals from N-
Received: May 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01575
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Letter
acylpyrroles,1−3 including the role of twist on the reactivity.
Collectively, our study opens an avenue for generating acyl-metal
intermediates from planar, electronically activated amides for a
range of catalytic coupling reactions via acyl and decarbonylative
pathways.
Scheme 1. Boronic Acid Scope in the Pd-NHC-Catalyzed
Cross-Coupling of N-Acylpyrroles
a b
,
Recently, our laboratory introduced new protocols for cross-
coupling of sterically activated amides by ground-state resonance
destabilization.9h−m In this context, we examined the reactivity of
sterically distorted N-acyl-2,5-dimethylpyrrole (<5% yield,9h τ =
39.7°; χN = 8.4°,15 Winkler−Dunitz distortion parameters). We
questioned whether electronic activation of nitrogen through
delocalization of Nlp into the π-electron system of the pyrrole
ring16 may be sufficient to selectively insert palladium into the
amide N−C bond in the absence of coordination or steric
distortion, resulting in a general process.
After very extensive optimization, we found that Pd-NHC
catalysis is indeed capable of promoting the desired reaction
[(IPr)Pd(cinnamyl)Cl, 6 mol %, 4-Tol-B(OH)2, 2.0 equiv,
K2CO3, 3.0 equiv, THF, 110 °C]. Selected optimization results
are summarized in Table 1. Of particular note, Pd-PR3 systems
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (2.0 equiv), [Pd] (6 mol
b
%), K2CO3 (3.0 equiv), THF (0.50 M), 110 °C, 15 h. Isolated yields.
a
Table 1. Optimization of N-Acylpyrrole Cross-Coupling
diverse boronic acids, including neutral (3a), electron-rich (3b−
3c), electron-withdrawing (3d), sterically hindered (3e−3f), and
heterocyclic boronic acids (3g). Cross-coupling with 4-methoxy-
carbonylphenyl boronic acid proceeds in unoptimized 34% yield
(not shown). 4-Cyanophenylboronic acid is not tolerated. At the
present stage, nitrophenyl has not been tested. Moreover,
conjugated aromatic (3h) and challenging 2-substitued hetero-
aromatic boronic acids (3i) are well-tolerated, delivering the
desired biaryl ketones in good to excellent yields.
Importantly, amides containing electron-rich (3b−3c) and
-withdrawing (3d) substituents at the conjugating 4-position of
the aromatic ring are compatible with the reaction conditions
(Scheme 2). Meta-substitution with electronically diverse
functional groups is well-tolerated (3j−3k). The reaction scope
could be further extended to medicinally relevant F-containing
(3l), sterically hindered (3m), heterocyclic (3n), and conjugated
4-biphenyl amides (3o). Interestingly, in the latter case the
deamidative reduction was notobserved, even thoughthe process
b
entry
catalyst
ligand
base
solvent
yield (%)
1
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCy3HBF4
PCy3HBF4
PPh3
K2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KF
THF
dioxane
THF
<2
<2
<2
<2
<2
<2
<2
82
57
92
<2
<2
<2
<2
<2
<2
56
2
3
4
PPh3
DMF
NMP
THF
5
PPh3
6
PnBu3
7
IPrHCl
THF
8
(IPr)Pd(allyl)Cl
THF
9
(SIPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
THF
10
11
12
13
14
15
16
THF
dioxane
toluene
THF
THF
KOH
THF
Scheme 2. Amide Scope in the Pd-NHC-Catalyzed Cross-
a
NaOtBu
K2CO3
THF
Coupling of N-Acylpyrroles
c
17
THF
a
Conditions: amide (1.0 equiv), R−B(OH)2 (2.0 equiv), catalyst (6
mol %), base (3.0 equiv), solvent (0.50 M), 110 °C, 15 h. Entries 1−6:
b
c
[Pd] (3 mol %), ligand (6 mol %). GC/1H NMR yields. [Pd] (3 mol
%).
were found ineffective as catalysts for amide N−C cross-coupling
(entries 1−6). We hypothesize that strong σ-donation of the
NHC ligand in facilitating oxidative addition is critical for the N−
C coupling reactivity. Evaluation of different Pd-NHC catalysts
revealed (IPr)Pd(cinnamyl)Cl to be optimal (entries 7−10). At
present, 110 °C is required for the coupling. The choice of base
and solvent had a dramatic effect on the reaction efficiency
(entries 10−16). Other bases (K3PO4, KF, KOH, NaO-tBu) and
solvents (dioxane, toluene) provided inferior results compared to
K2CO3/THF.14
Having identified the optimal conditions, we next evaluated the
scope of the reaction with respect to the boronic acid component
(Scheme 1). As shown, these conditions are compatible with
a
See Scheme 1 footnotes a and b.
B
DOI: 10.1021/acs.orglett.7b01575
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Letter
planar amides is advantageous due to higher stability to
nucleophilic capture.
Scheme 3. Cross-Coupling of N-Acylpyrazole
Kinetic studies were performed to further evaluate the relative
reactivityofamides1a,1k,1lundergoingthecoupling(Scheme7;
see Supporting Information, SI). Initial rates revealed the
following order of reactivity: (1a) (νinitial = 2.1 × 10−1 mM s−1)
≈ (1k) (νinitial = 2.2 × 10−1 mM s−1) ≈ (1l) (νinitial = 3.6 × 10−1
mM s−1). (1) The rates parallel relative reactivity under the
thermodynamic conditions. (2) All three amides react at similar
rates, irrespective of electronic properties and amide twist.
Collectively, the rate-determining step may not involve N−C
activation under these reaction conditions. Transmetalation is
generally considered as the rate-determining step in Suzuki−
Miyaura couplings of aryl electrophiles.18
is facilitated by conjugated aromatics,10 demonstrating the
complementary scope of both reaction protocols.
We were pleased to find that the coupling of N-acylpyrazole
proceeded uneventfully without modification of the reaction
conditions (Scheme 3), despite different electronic properties of
the amide bond,16 highlighting the versatility of Pd-NHC.
Intriguingly, the present system can be applied to couple the
twisted N-acyl-2,5-Me2-pyrrole (Scheme 4).15 The successful
coupling of sterically distorted 1l under the same conditions as
planar 1a suggests that amide twist may not be required for N−C
activation.
Scheme 7. Amides Employed in Kinetic and Computational
Studies
Scheme 4. Cross-Coupling of Twisted Amide
Primary amides are ubiquitous intermediates and target
compounds in pharmaceutical and organic materials applica-
tions.5,6 Since N-acylpyrroles can be readily prepared from
primary benzamides,13 our method offers a rapid entry to acyl-
metal intermediates from unactivated primary amides (Scheme
5). Catalytic methods for direct coupling of unactivated primary
amides using Pd are currently absent in the literature.1,9n
Scheme 5. Synthesis of N-Acylpyrroles from 1° Amides
Figure 3. Rotational profile (1a, ΔE, kcal/mol, vs O−C−N−C [deg]).
Computations were employed to gain insight into the
energetics of the amide bond undergoing N−C cleavage (Figure
3; see SI). N-Acylimidazole 1m (Scheme 7) was included for
comparison. The coupling of 1m was unproductive under all
conditions tested. It is well-established that N-coordination at
C2/C3 in N-acylpyrazoles and imidazoles is facile.16
Competition studies were performed to establish the relative
reactivity (Scheme 6). As shown, similar relative reactivity of 1b
and 1k under thermodynamic conditions of the experiment was
found. The intramolecular competition between planar N-
acylpyrrole (1b) and twisted N-acyl-2,5-Me2-pyrrole (1l) gave a
mixture of products, resulting from background nucleophilic
transamidation of the twisted amide bond.17 Clearly, the use of
(1) Resonance energy (RE) determined by the COSNAR
method19 indicates that the conjugation is in the following
order: 1a, 9.3 kcal/mol; 1k, 7.8 kcal/mol; 1l, 2.8 kcal/mol.
As expected, RE in 1a and 1k is much lower than in planar
amides. RE in the twisted 1l is almost completely switched
off as a result of additional twist.
Scheme 6. Competition Experiments
(2) Rotational profiles in 1a and 1l along the O−C−N−C(Ar)
dihedral angle confirm amide planarity in 1a (the energy
minimum at ca. 10° O−C−N−C angle, τ = 14.44°; χN =
7.93°; Figure 3), and amide inverted profile in 1l (the
energy minimum at ca. 40° O−C−N−C angle, τ = 43.64°;
χN = 4.04°; see SI).
(3) Resonance energy in N-ring protonated 1k and 1m are as
follows: 1k, 4.8 kcal/mol; 1m, 1.0 kcal/mol (neutral 1m,
RE of 7.8 kcal/mol). As expected, N-coordination at the
heterocyclic ring significantly weakens amidic resonance.20
(4) The difference between N-/O-protonation affinities
(ΔPA) indicates that 1a and 1l strongly favor coordination
C
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amide cross-coupling, see: (b) Ruider, S. A.; Maulide, N. Angew. Chem.,
Int. Ed. 2015, 54, 13856.
at the amide oxygen (vs amide nitrogen, ΔPA = 21.4, 11.0
kcal/mol). However, protonation of the ring nitrogen is
(7) For representative examples of N−C activation, see: (a) Blakey, S.
B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 6046. (b) Buszek, K.
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favored in 1k and 1m (ΔPA = 13.1, 26.1 kcal/mol).
Overall, the structural and energetic parameters of the amide
bond combined with kinetic studies suggest that (1) N−C
activation is not the rate limiting step in the coupling; (2)
electronic destabilization of nN → π*CO conjugation enables
selective N−C activation in N-acylpyrroles and pyrazoles.
In summary, we have achieved the first catalytic C−C bond
formation from planar amides enabled by electronic activation of
the amide N atom in N-acylpyrroles and pyrazoles. The method is
operationally convenient and exploits N-acylpyrroles as Weinreb
amideequivalents. ThesefindingshighlighttheutilityofPd-NHC
catalysis14 in selective activation of inert amide N−C bonds. The
direct synthesis of N-acylpyrroles from primary amides opens the
doorforcatalyticcouplingofunactivatedprimaryamidesbymetal
catalysis. Most importantly, the study provides an avenue for a
plethora of catalytic cross-coupling reactions via acyl-metal
intermediates from planar, electronically activated amides.
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01575.
■
S
Experimental procedures and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Guangrong Meng: 0000-0002-3023-0654
Michal Szostak: 0000-0002-9650-9690
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. The
Bruker 500 MHz spectrometer used in this study was supported
by an NSF-MRI grant (CHE-1229030). We thank the Wrocław
Center for Networking and Supercomputing (grant number
WCSS159).
(10) Dey, A.; Sasmal, S.; Seth, K.; Lahiri, G. K.; Maiti, D. ACS Catal.
2017, 7, 433.
(11) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem., Int. Ed. 2002,
41, 3188 and references cited therein.
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D
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