N-acylsaccharins: Stable electrophilic amide-based acyl transfer reagents in Pd-catalyzed Suzuki-Miyaura coupling via N-C cleavage

Article abstract of DOI:10.1021/acs.orglett.6b01836

The development of efficient catalytic methods for N-C bond cleavage in amides remains an important synthetic challenge. The first Pd-catalyzed Suzuki-Miyaura cross-coupling of N-acylsaccharins with boronic acids by selective N-C bond activation is reported. The reaction enables preparation of a variety of functionalized diaryl and alkyl-aryl ketones with broad functional group tolerance and in good to excellent yields. Of general interest, N-acylsaccharins serve as new, highly reactive, bench-stable, economical, amide-based, electrophilic acyl transfer reagents via acyl-metal intermediates. Mechanistic studies strongly support the amide N-C(O) bond twist as the enabling feature of N-acylsaccharins in the N-C bond cleavage.

Full text of DOI:10.1021/acs.orglett.6b01836

Letter
pubs.acs.org/OrgLett
N‑Acylsaccharins: Stable Electrophilic Amide-Based Acyl Transfer
Reagents in Pd-Catalyzed Suzuki−Miyaura Coupling via N−C
Cleavage
†
†
†,‡
‡
†
§
Chengwei Liu, Guangrong Meng, Yongmei Liu, Ruzhang Liu, Roger Lalancette, Roman Szostak,
and Michal Szostak*
,†
†
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
College of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Road, Yangzhou 225002, China
Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
‡
§
*
S Supporting Information
ABSTRACT: The development of efficient catalytic methods for
N−C bond cleavage in amides remains an important synthetic
challenge. The first Pd-catalyzed Suzuki−Miyaura cross-coupling of
N-acylsaccharins with boronic acids by selective N−C bond
activation is reported. The reaction enables preparation of a variety
of functionalized diaryl and alkyl-aryl ketones with broad functional
group tolerance and in good to excellent yields. Of general interest,
N-acylsaccharins serve as new, highly reactive, bench-stable, economical, amide-based, electrophilic acyl transfer reagents via acyl-
metal intermediates. Mechanistic studies strongly support the amide N−C(O) bond twist as the enabling feature of N-
acylsaccharins in the N−C bond cleavage.
he incorporation of the acyl group into organic molecules is
T
a fundamental transformation in biological and synthetic
1
,2
chemistry. In this context, the transition-metal-catalyzed
acylation of organometallic reagents has emerged as a powerful
strategy to produce functionalized ketones with numerous
applications in pharmaceutical, dye, and agrochemical indus-
3
,4
tries. A number of methods and reagents have been developed
over the past years, including palladium- and nickel-catalyzed
cross-coupling reactions of acyl chlorides, thioesters, and
5
anhydrides. By contrast, the transition-metal-catalyzed acylation
6
by N−C cleavage in amides represents a significant challenge
due to n → π* conjugation and the resulting partial double
N
CO
7
bond character of the amide bond. The amide bond resonance
prohibits direct metal insertion into the N−C(O) bond in planar
amides. As a consequence, there have been very few reports on
8
−10
the cross-coupling of amides with organometallic reagents
despite the potential versatility of amides as acylating reagents
and the fundamental role of amides in biology and medicinal
7
b
chemistry. In 2015, in consideration of the amidic resonance,
our laboratory introduced the concept of amide bond ground-
state destabilization to enable a range of metal-catalyzed
transformation of amides by N−C cleavage in generic C−C
Figure 1. (a) Activation of amides by N−C cleavage. (b) Saccharins as
functional group transfer reagents: previous and this work.
Continuing this theme, we became interested in using N-
8
acylsaccharins as selective amide-based acyl transfer reagents in
bond-forming reactions (Figure 1A). Independently, palladium-
1
2
transition-metal catalysis. The use of halo-saccharins as
and nickel-catalyzed cross-coupling of amides with boronic
13
9
electrophilic reagents has been widely studied. Recently,
some notable examples have advanced the scope of saccharins
as efficient functional group transfer reagents for trifluoromethyl-
acids and nickel-catalyzed borylation by N−C cleavage have
1
0
been developed. Unsurprisingly, all amides utilized to date
1
1
contain destabilized (twisted) amide bonds, while N-
glutarimide amides introduced by our laboratory showed thus
far the highest reactivity in a range of cross-coupling reactions
Received: June 22, 2016
8
employing Pd, Rh, and Ni catalysis.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01836
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
4a
14b
14c
thiolation, formylation,
and alkoxycarbonylation reac-
Table 1. Optimization of Pd-Catalyzed Suzuki−Miyaura
a
tions (Figure 1B). Herein, we detail the first example of
Cross-Coupling of N-Acylsaccharins by N−C Cleavage
1
5
palladium-catalyzed Suzuki−Miyaura cross-coupling of N-
acylsaccharins with boronic acids by N−C bond cleavage. N-
Acylsaccharins serve as new, highly reactive, bench-stable,
economical, amide-based, electrophilic acyl transfer reagents
for C−C bond forming reactions via acyl-metal intermediates by
selective N−C bond cleavage. This finding opens the door for
using N-acylsaccharins in a wide range of transition-metal-
entry
catalyst
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
PCy HBF4
THF
THF
THF
THF
THF
dioxane
DCE
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
97
61
56
57
77
68
44
18
81
<5
91
89
30
50
45
35
79
87
3
PCy HBF4
3
3
−5
catalyzed reaction manifolds.
N-Acylsaccharins offer several major advantages: (a) saccharin
Pd(dba)2
PCy HBF4
3
Pd (dba)3
2
PCy HBF4
3
is a cheap, widely accessible commodity chemical produced on
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCy HBF4
3
16
>
(
50,000 ton scale annually with a bulk price of <$0.10/gram;
b) the presence of an electron-withdrawing sulfonyl moiety
results in an enhanced electrophilicity of the acyl-carbonyl group;
c) saccharin is commonly used as an artificial sweetener and is
PCy HBF4
3
PCy HBF4
3
PCy HBF4
3
b
(
9
PCy HBF4
3
virtually nontoxic; (d) N-acylsaccharins are bench-stable and
easy to handle crystalline solids, with no decomposition observed
over a period of 3 months at ambient conditions; (e) the
geometric properties of N-acylsaccharins (vide infra) allow fine-
tuning of the reactivity of the amide N−C bond by distortion,
resulting in a new class of highly chemoselective acyl transfer
reagents with orthogonal functional group tolerance to other
carbonyl groups, while avoiding the handling of moisture
sensitive and corrosive halides in transition metal catalyzed
10
11
12
13
14
15
16
−
PPh3
PCy Ph
2
DPPP
DPPB
DPPE
DPPM
c
17
d
PCy HBF4
3
18
PCy HBF4
3
1
7
manifolds.
a
Conditions: 1 (1 equiv), 4-Tol-B(OH) (2.0 equiv), catalyst (3 mol
2
N-Acylsaccharins are easily synthesized in an average yield of
7% by the reaction of saccharin with acyl chlorides in N,N-
%), ligand (12 mol %), K CO (2.5 equiv), H BO (2.0 equiv), 65 °C,
2 3 3 3
b c d
8
15 h. ligand (3 mol %). Without H BO . 4-Tol-B(OH)2 (1.2
3 3
1
8
dimethylacetamide following the known procedure and
isolated by recrystallization (see Supporting Information).
We began our studies by examining the coupling of N-
benzoylsaccharin with 4-tolylboronic acid under a variety of
conditions. Table 1 summarizes key results from the
optimization experiments. The desired coupling proceeds in an
equiv).
handles (3j) and medicinally relevant heterocycles (3k−3l). The
scope of the amide component is also broad. Electron-rich (3b′−
3c′) and electron-deficient (3d′) N-acylsaccharins provided the
desired product in high yield (vide infra). Notably, electrophilic
functional handles such as fluoro- (3m), chloro- (3n), ester-
(3o), and nitro- (3p) at the para-position are perfectly
accommodated. Moreover, ortho-coordinating (3q), sterically
hindered (3e′), and heterocyclic (3r) amides underwent smooth
acylation. Finally, 1° (3s) and 2° (3t) alkyl amides are efficient
coupling partners, affording the valuable alkyl aryl ketones in
good yields. Overall, the scope of the cross-coupling of N-
acylsaccharins compares very favorably with other examples of
Suzuki cross-coupling by the amide N−C cleavage reported to
excellent >95% yield in the presence of Pd(OAc) (3 mol %),
2
PCy HBF (12 mol %), K CO (2.5 equiv), and H BO (2.0
3
4
2
3
3
3
equiv) in THF at 65 °C (entries 1−10). Interestingly, triaryl
phosphines can also be successfully employed as ligands in the
reaction (entries 11−16), suggesting higher reactivity of N-
8
acylsaccharins than N-glutarimide amides. We determined that
the conditions employing PCy Ph proved to be the most general
2
across the range of substrates examined, and subsequently used
PCy Ph in the substrate scope studies. The use of structurally
2
8
,9
related PCyPh was ineffective, revealing subtleties of our
date. Importantly, the present process is advantageous in terms
of economy and availability of saccharin as an acyl-transfer
2
protocol. Several other optimization results deserve a comment.
1
,2,16
A high yield is obtained using PPh , indicative of facile Pd(0)
reagent.
3
3
−6
insertion into the N−C bond.
Similarly, >80% yield is
To gain insight into the role of amide bond twist on the high
reactivity of N-acylsaccharins, the X-ray structure of 1a was
determined (Figure 2). The X-ray structure confirms that 1a
obtained with an equimolar Pd/ligand ratio (entry 9), suggesting
8d
high reactivity of the N−C bond toward metal insertion. The
use of acid is critical for high reactivity, likely as a result of
switchable O-/O-coordination (entry 17) (vide infra).
11
contains a highly distorted amide bond (τ = 23.0°, χ = 12.5°,
N
1
9
21
χC = 1.0°). The N−C(O) and CO bond lengths are 1.421
Importantly, full selectivity for N−C insertion/coupling is
observed under the optimized conditions, with products
and 1.208 Å. The acyl CO bond is antiperiplanar to the N−
C(O) bond and bisects the O−S−O angle.
resulting from C−SO insertion and decarbonylation not
Computations were employed to probe the role of amide
resonance in the high reactivity of N-acylsaccharins: (1) the
rotational profile of 1a determined by systematic rotation along
the O−C−N−C dihedral angle (Figure 3) shows ground state
distortion in N-acylsaccharins. The energy minimum is located at
2
2
0
detected.
With the optimized conditions in hand, the scope of the
reaction was next investigated (Table 2). As shown, a variety of
boronic acids can be employed, yielding the desired ketone
products with high efficiency, including electron-donating (3b−
a ca. 150° O−C−N−C angle (τ = 27.26°; χ = 8.88°). The
N
3
c), electron-withdrawing (3d), and sterically hindered (3e−3g)
energy maximum is located at a ca. −20° O−C−N−C dihedral
boronic acids. Moreover, highly electron-rich (3h) and electron-
deficient (3i) boronic acids are competent coupling partners. Of
particular interest are the products containing electrophilic
angle (τ = 10.96°; χ = 17.46°) in a 1,3
eclipsing
N
(CO/CO)
interaction, as expected. The rotational barrier was determined to
be 4.87 kcal/mol. (2) The resonance energy (RE) of 1a
B
DOI: 10.1021/acs.orglett.6b01836
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Pd-Catalyzed Suzuki−Miyaura Cross-Coupling of N-Acylsaccharins by N−C Cleavage: Substrate Scope
a
b
1
(1.0 equiv), Ar−B(OH) (2.0 equiv), Pd(OAc) (3 mol %), ligand (12 mol %), K CO (2.5 equiv), H BO (2.0 equiv), THF, 65 °C. 120 °C.
2
2
2
3
3
3
See Supporting Information for details.
Figure 2. (a) Crystal structure of 1a. (b) Inset shows Newman
projection along the N−C(O) bond. Selected bond lengths (Å) and
angles (deg): N1−C8, 1.421(3); C8−O1, 1.208(3); C8−C9, 1.487(3);
C9−C8−N1−S1, 162.8(1); O1−C8−N1−C1, 151.3(2); O1−C8−
N1−S1, −16.3(3); C9−C8−N1−C1, −29.7(3).
Figure 3. Rotational profile (1a, ΔE, kcal/mol, vs O−C−N−C [deg]).
oxygen (ΔPA = 11.8 kcal/mol), and that the protonation of the
N-acyl group is favored over the ring amide (ΔPA = 5.0 kcal/
determined by the COSNAR method indicates that the
19
conjugation in 1a practically disappears (RE = 2.0 kcal/
mol) and sulfonamide oxygens (ΔPA = 5.3, 10.9 kcal/mol).
1
9b
mol). (3) The difference between N-/O-protonation affinities
ΔPA) in 1a verifies that N-saccharins favor protonation at
Overall, the structural and energetic parameters of the amide
bond in N-acylsaccharins strongly support ground-state
(
C
DOI: 10.1021/acs.orglett.6b01836
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
1
destabilization as the enabling factor for N−C activation under
mild conditions.
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(
3
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In conclusion, we have developed N-acylsaccharins as new,
amide-based, electrophilic reagents for transition-metal-cata-
lyzed acyl transfer reactions by selective N−C bond cleavage.
These reagents are shelf-stable, easy-to-use, and readily available
from the cheap and benign saccharin. The high reactivity was
demonstrated in the Pd-catalyzed Suzuki−Miyaura cross-
coupling to give a variety of functionalized ketones. Mechanistic
studies support the amide bond distortion as a chemoselectivity-
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determining feature in N−C cleavage. Studies to expand the
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ASSOCIATED CONTENT
■
*
S
Supporting Information
́
J. Chem. Rev. 2013, 113, 5701.
(
The Supporting Information is available free of charge on the
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a) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
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AUTHOR INFORMATION
■
Corresponding Author
2
(
(
*E-mail: michal.szostak@rutgers.edu.
Notes
(
The authors declare no competing financial interest.
M. A. H. The Greening of Pharmaceutical Engineering, Practice, Analysis,
and Methodology; Wiley: Hoboken, NJ, 2015.
ACKNOWLEDGMENTS
(17) Beller, M.; Blaser, H. U. Top. Organomet. Chem. 2012, 42, 1.
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Financial support was provided by Rutgers University. The
Bruker 500 MHz spectrometer used in this study was supported
by the NSF-MRI Grant (CHE-1229030). We thank the Wrocław
Center for Networking and Supercomputing (grant number
WCSS159). Y.L. thanks for a scholarship from the Priority Aca-
demic Program Development of Jiangsu Higher Educatio-
n−Yangzhou University and the National Natural Science
Foundation of China (No. 21472616).
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2015, 51, 6395. (d) Szostak, R.; Aube,
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DOI: 10.1021/acs.orglett.6b01836
Org. Lett. XXXX, XXX, XXX−XXX