Acyl and Decarbonylative Suzuki Coupling of N-Acetyl Amides: Electronic Tuning of Twisted, Acyclic Amides in Catalytic Carbon-Nitrogen Bond Cleavage

Article abstract of DOI:10.1021/acscatal.8b02815

We report the Pd-catalyzed acyl and the Ni-catalyzed biaryl Suzuki-Miyaura cross-coupling of N-acetyl-amides with arylboronic acids by selective N-C(O) cleavage. Activation of the amide bond by N-acylation provides electronically destabilized, acyclic, nonplanar amide, which readily undergoes cross-coupling with a wide range of boronic acids to produce biaryl ketones or biaryls in a highly efficient manner. Most crucially, the presented results introduce N-acetyl-amides as reactive acyclic amides in the emerging manifold of transition-metal-catalyzed amide cross-coupling. The scope and origin of high selectivity are discussed. Mechanistic studies point to remodeling of amidic resonance and amide bond twist as selectivity determining features in a unified strategy for cross-coupling of acyclic amides. Structural studies, mechanistic investigations as well as beneficial effects of the N-acyl substitution on cross-coupling of amides are reported.

Full text of DOI:10.1021/acscatal.8b02815

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Letter
Acyl- and Decarbonylative Suzuki Coupling of N-
Acetyl Amides: Electronic-Tuning of Twisted, Acyclic
Amides in Catalytic Carbon–Nitrogen Bond Cleavage
Chengwei Liu, Guangchen Li, Shicheng Shi, Guangrong Meng,
Roger A Lalancette, Roman Szostak, and Michal Szostak
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02815 • Publication Date (Web): 23 Aug 2018
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ACS Catalysis
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Acyl- and Decarbonylative Suzuki Coupling of N-Acetyl Amides:
Electronic-Tuning of Twisted, Acyclic Amides in Catalytic Carbon–
Nitrogen Bond Cleavage
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Chengwei Liu,†,§ Guangchen Li,†,§ Shicheng Shi,† Guangrong Meng,† Roger Lalancette,† Roman Szos-
tak,‡ 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
Supporting Information
KEYWORDS: amides, N–C activation, cross-coupling, Suzuki-Miyaura coupling, decarbonylation, biaryl coupling
ABSTRACT: We report the Pd-catalyzed acyl and the Ni-catalyzed biaryl Suzuki-Miyaura cross-coupling of N-acetyl-amides with
arylboronic acids by selective N–C(O) cleavage. Activation of the amide bond by N-acylation provides electronically-destabilized,
acyclic, non-planar amide, which readily undergoes cross-coupling with a wide range of boronic acids to produce biaryl ketones or
biaryls in a highly efficient manner. Most crucially, the presented results introduce N-acetyl-amides as reactive acyclic amides in
the emerging manifold of transition-metal-catalyzed amide cross-coupling. The scope and origin of high selectivity are discussed.
Mechanistic studies point to re-modeling of amidic resonance and amide bond twist as selectivity determining features in a unified
strategy for cross-coupling of acyclic amides. Structural studies, mechanistic investigations as well as beneficial effects of the N-
acyl substitution on cross-coupling of amides are reported.
Cross-coupling reactions of amides have been established as a
powerful route to functionalization of the ubiquitous amide
bond essential in organic synthesis (Figure 1).1,2 Direct inser-
tion of a transition metal into the traditionally-inert amide
bond generates a versatile acyl-metal intermediate A as an
enabling platform for chemical synthesis.3,4 Amides are partic-
ularly attractive targets for metal-induced functional-group
interconversion5 due to their fundamental significance as ver-
satile synthetic intermediates and central role as key building
blocks in the production of biologically-active compounds.6, 7
As a result, converting common amides into high value func-
tional groups has a transformative effect on synthetic design.
C(O) cross-coupling, which limits, in particular, the scope of
valuable decarbonylative processes of amides to N-cyclic am-
ides.17–22 Thus, the development of new amide precursors that
are compatible with various reaction pathways is critical to
fully exploit the potential of amides in cross-coupling.1–4
Herein, we report the first Pd-catalyzed acyl and Ni-
catalyzed decarbonylative Suzuki-Miyaura cross-coupling of
N-acetyl-amides with arylboronic acids (Figure 2). Most cru-
cially, the presented results introduce N-acetyl-amides as the
most reactive acyclic amides developed thus far in the emerg-
ing manifold of transition-metal-catalyzed amide cross-
coupling. Notable features of our findings include: (i) unprec-
edented N–C(O) cleavage reactivity induced by the acyl group
(ii) exceptionally high stability under the reaction conditions
that avoids shutting-off N–X scission, (iii) reagent-controlled
fully chemoselective divergent23 acyl and decarbonylative
coupling, (iv) the first example of the biaryl Suzuki-Miyaura
cross-coupling24 of simple acyclic amides, (v) in contrast to
the recently reported precursors, versatile synthesis from sec-
ondary and primary amides that engenders a broad generality
of this reactivity platform. As a key design element, structural
In principle, transformations at the C(acyl) amide bond are
founded on the steric and electronic re-modeling of amidic
resonance that further benefits from trigonal nitrogen geome-
try enabling controlled variation of sterics and amidicity.8–10
The development of well-defined amide precursors permits a
rational approach to cross-coupling reactions of amides and
sets the stage for methodological advances.11–16 One main ob-
stacle is that the cleavage of the N–X bond (X = Ts, Boc) is a
major side reaction in Pd(0) and Ni(0)-catalyzed amide N–
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and mechanistic studies point to re-modeling of amidic reso-
biaryl ketone 3 (Table 1, entry 1). Furthermore, the reaction at
40 °C afforded 3 in 82% yield (Table 1, entry 2), demonstrat-
ing the superior reactivity of N-Ac-amide 1 over other precur-
sors.2 Selected optimization results are summarized in Table 1.
Exploration of different solvents and bases revealed that a
nance9,10 and amide bond twist8 as selectivity determining
features in a unified strategy for cross-coupling of acyclic
amides. We expect N-acetyl amides as generic precursors in
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Table 1. Optimization of Palladium-Catalyzed Cross-
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Coupling of N-Ac Amides by N–C Cleavagea
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Figure 1. Metal-catalyzed activation of amides.
yield
entry
catalyst
ligand
base
solvent
(%)
>98
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<2
<2
<2
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<5
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2b
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
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
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy2Ph
K2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
Na2CO3
K2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
toluene
THF
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4
dioxane
toluene
THF
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dioxane
THF
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dioxane
toluene
THF
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11c
12c
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22d
23e
24f
25g
THF
THF
Figure 2. (a) Acyl and decarbonylative cross-coupling of acyclic amides.
(b) Twist-enabled activation of the amide bond (this work).
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
amide bond cross-coupling to greatly expand the scope of
direct functionalization of amides due to the inherent steric
and electronic advantages that determine the reactivity and
selectivity of these processes.2,9,10
PCyPh2
PPh3
P(o-Tol)3
P(n-Bu)3
Recently, our laboratory introduced N-acyl-glutarimides for
the cross-coupling reactions by N–C(O) amide cleavage.22
These cyclic amide precursors have now been established as
by far the most reactive amide derivatives in the powerful
amide bond cross-coupling manifold, enabling the develop-
ment of more than 10 previously unknown catalytic modes of
reactivity of the amide bond.1–4,22 Despite the success of N-
acyl-glutarimides, these precursors lack generality in that they
cannot be prepared from common and readily available prima-
ry and secondary amides. A critical design feature of N-acyl-
glutarimides is the combination of amide bond twist and reso-
nance destabilization in a rotationally-inverted amide scaf-
fold.9b Drawing from our mechanistic insights,9d we envi-
sioned that glutarimide ring de-construction could retain the
capacity of amides to undergo facile metal insertion under
mild conditions (Figure 2B), while enabling a broad range of
common acyclic amides to be employed as viable precursors
to acyl-metal intermediates A in the coupling (Figure 1). To
test this concept, we selected acyl Suzuki-Miyaura cross-
coupling as a representative transformation.
P(t-Bu)3
XPhos
XantPhos
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
aConditions: amide (0.20 mmol, 1 equiv), Ar-B(OH)2 (0.40 mmol, 2.0
equiv), catalyst (3 mol%), ligand (12 mol%), base (2.5 equiv), H3BO3 (2.0
equiv), solvent (0.20 M), 60 °C, 15 h. b40 °C. c Without H3BO3. dligand (3
mol%). eligand (6 mol%). fAr-B(OH)2 (1.2 equiv). gAr-B(OH)2 (1.5 equiv).
See SI for details.
combination of K2CO3 and toluene was optimal (entries 3-10).
Interestingly, we found that the addition of boric acid to pre-
sumably induce switchable N-/O-activation of the amide
bond9b and prevent protodeboronation24 had a positive effect
on the coupling (entries 11-13). We hypothesize that H3BO3
promotes the coupling by protonation of the acyl oxygen atom,
which further decreases amidic resonance and activates the
amide bond towards the coupling. Most notably, the nature of
the ligand had a profound impact on the coupling and PCy3
proved to be the most effective (entries 14-21). This phosphine
emerges as a privileged ligand in Pd-catalyzed amide bond
activation, presumably due to highly electron-rich nature and
After extensive optimization, we established than the reac-
tion of N-acetyl amide 1 with 4-Tol-B(OH)2 (2.0 equiv) in the
presence of Pd(OAc)2 (3 mol%) and PCy3HBF4 (12 mol%) in
combination with K2CO3 (2.5 equiv) and H3BO3 (2.0 equiv) in
toluene at 60 °C resulted in a quantitative conversion to the
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ACS Catalysis
well-fitted steric impact on the Pd center (cf. t-Bu3P).3 Exami-
and functional materials standpoints27 deliver the biaryl ketone
products in good to excellent yields.
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nation of different Pd/ligand stoichiometry revealed that effi-
cient coupling ensues with a close to 1:1 Pd:ligand ratio, con-
sistent with facile insertion/transmetallation in the catalytic
cycle (entries 22-23). Finally, even when the amount of bo-
ronic acid was decreased to 1.2-1.5 equiv, the desired ketone
was obtained in good yields at 60 °C (76-83%), providing an
entry point for future studies (entries 24-25), and consistent
with a rate-determining transmetallation. Importantly, under
the optimized conditions, scission of the alternative N–C
We next turned out attention to the scope of N-acetyl-
amides that can participate in this coupling (Scheme 2). As
shown, substrates with electron-donating (3b’-c’) and with-
drawing (3d’-f’, 3q-t) substituents reacted well under our op-
timized conditions. Moreover, an aryl chloride (3r) was toler-
ated under the reaction conditions, providing handle for se-
quential cross-coupling. Of note, this rare selectivity28 in tran-
sition-metal-catalyzed amide activation (amide > Cl) indicates
high and synthetically-useful N–C(O) coupling reactivity of
N-acetyl amides. Perhaps most notably this method can be
9
Scheme 1. Boronic Acid Scope in the Palladium-Catalyzed
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Cross-Coupling of N-Ac Amidesa,b
Scheme 2. Amide Scope in the Palladium-Catalyzed Cross-
Coupling of N-Ac Amidesa,b
aConditions: amide (0.20 mmol, 1.0 equiv), Ar-B(OH)2 (0.40 mmol, 2.0
equiv), Pd(OAc)2 (3 mol%), PCy3HBF4 (12 mol%), K2CO3 (2.5 equiv),
H3BO3 (2.0 equiv), toluene (0.20 M), 60 °C, 15 h. bIsolated yields.
cPhB(OH)2 (1.2 equiv). dPhB(OH)2 (3.0 equiv), K2CO3 (4.5 equiv), 120
°C. See SI for details.
aConditions: amide (0.20 mmol, 1.0 equiv), Ar-B(OH)2 (0.40 mmol, 2.0
equiv), Pd(OAc)2 (3 mol%), PCy3HBF4 (12 mol%), K2CO3 (2.5 equiv),
H3BO3 (2.0 equiv), toluene (0.20 M), 60 °C, 15 h. Isolated yields. 120
°C. See SI for details.
b
c
applied to a wide variety of amides bearing electrophilic
groups, including nitro (3s), cyano (3t), ester (3e’) and ketone
(3f’) that would be incompatible with the classic Weinreb
ketone synthesis,25 demonstrating a significant advantage from
the practical standpoint. Furthermore, ortho-fluoro-substitution
(3u) poised for derivatization by SNAr is well-tolerated. Final-
ly, polyaromatic amides prone to decarbonylation (3j’)12d as
well as heterocyclic amides (3v) delivered the desired product
in good yields. In general, other by-products than the PhN(Ac)
leaving group have not been observed. At the present stage of
reaction development aliphatic amides are beyond the scope of
the reaction. Alkyl boronic acids as well as N-heterocycles,
such as pyridine, indole and quinoline, have not been tested.
Future studies will be aimed at expanding the substrate scope
of amide bond cross-coupling.
bond shutting-off the reactivity was not observed, indicating
high propensity of the N-acyl-amide to undergo chemoselec-
tive N–C(O) oxidative addition.
With optimal reaction conditions in hand, we next turned
our attention to the scope of boronic acids that can participate
in this reaction (Scheme 1). As shown, a wide range of bo-
ronic acids bearing electron-neutral (3a), electron-donating
(3b-c) and electron-withdrawing (3d-g) substituents is com-
patible with this coupling. Particularly noteworthy is that elec-
trophilic-functional groups that would be problematic in the
classic organometallic additions,25 including esters (3e), ke-
tones (3f) and aldehydes (3g) are well-tolerated. Furthermore,
steric-hindrance (3h-i), polyaromatics (3i-j) and electrophilic
nitro (3l) and cyano groups (3m) can be readily employed in
this coupling. Finally, fluorinated boronic acids (3o) and het-
eroaromatics (3p) important from the medicinal chemistry26
We were pleased to find that the method can also be applied
to the coupling of challenging N-Ac/alkyl amides (Scheme 3),2
demonstrating a broad generality of the N-acetyl activation
platform.
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Furthermore, the coupling using Pd-NHC catalysts is feasi-
ble (Scheme 4).29 The use of well-defined Pd(II)-NHC
prectalysts provides significant advantages in cross-coupling
manifolds.30
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3
4
5
6
7
8
9
Turnover numbers (TON) of 970, 3100, 3500 were deter-
mined for the cross-coupling of amide 1a (Pd(OAc)2/PCy3,
0.10 mol%, 60 °C; 0.025 mol%, 60 °C; Pd-PEPPSI-IPr,
(IPr)Pd(cin)Cl, 0.025 mol%, 60 °C) (Scheme 5). This is the
highest TON determined for Pd-catalyzed amide N–C activa-
tion reported to date for both Pd-PR3 and Pd-NHC catalysts,29
clearly demonstrating the high activity and the advantage of
N-acetyl-amides in the Suzuki-Miyaura cross-coupling.
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To gain insight into the mechanism, preliminary experi-
ments were conducted (Scheme 6). (1) Electron-deficient am-
ides are inherently more reactive (4-CF3:4-MeO = 91:9). (2)
Electron-rich nucleophiles react preferentially (4-MeO:4-CF3
= 77:23). (3) The reactivity order with respect to the amide
activating group is as follows: N-Ac/R >> N-R/Ts, N-
Scheme 3. Cross-Coupling of N-Ac/Alkyl Amides
Scheme 7. Synthesis of N-Ac Amides from 1° or 2° Amides
Scheme 4. Cross-Coupling using Pd(II)-NHC Catalysts
R/Boc, N-Ar/R (anilide). Clearly, the high reactivity of N-
acyl-amides provides the advantage in the amide bond activa-
tion platform.
Scheme 5. Determination of TON in the Cross-Coupling of
N-Ac Amides
To further expand the synthetic utility of N-Ac-amides, we
demonstrated that N-Ac amides can be readily prepared from
unactivated secondary amides by chemoselective N-acylation
(Scheme 7). Since methods for the synthesis of secondary
amides from primary amides are well-established,31 the N-Ac-
amide reactivity platform provides rapid entry to acyl-metal
intermediates A (Figure 1) from common unactivated amides.
Hence, as a pivotal synthetic advantage, the amide bond cross-
coupling could thus benefit from engaging common amides in
this cross-coupling platform.
Having established the high reactivity of N-Ac-amides, we
next sought to demonstrate the generality of these amide pre-
cursors. Considering the tremendous importance of biaryl Su-
zuki-Miyaura cross-coupling in the field of organic synthe-
sis,24 we selected decarbonylative Suzuki-Miyaura coupling as
a representative transformation. Since thus far only one exam-
ple of decarbonylative Suzuki-Miyaura cross-coupling of am-
ides has been reported, we were attracted to this challenge.12b
The use of acyclic amides in biaryl Suzuki cross-coupling
would represent a significant advance for implementing the
biaryl transform in cross-coupling reactions.
Scheme 6. Competition Experiments
After extensive optimization (see SI for optimization de-
tails), we identified conditions to effect decarbonylative
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Scheme 8. Nickel-Catalyzed Suzuki-Miyaura Biaryl Synthesis through Cross-Coupling of N-Ac Amidesa,b
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b
c
aConditions: amide (1.0 equiv), Ar-B(OH)2 (1.5 equiv), Ni(PCy3)2Cl2 (5 mol%), base (4.5 equiv), dioxane (0.25 M), 150 °C, 15 h. Isolated yields. Ar-
B(OH)2 (3.0 equiv). See SI for details.
Suzuki-Miyaura cross-coupling of N-Ac-amides with exquisite
decarbonylation selectivity (Scheme 8). We found that a cata-
lytic system based on inexpensive, 3d transition metal, Ni,
[Ni(PCy3)2Cl2, 5 mol%] in the presence of Na2CO3 as a base in
dioxane at 150 °C provided optimum results. Other Ni(II)
precatalysts, bases and solvents were screened (see SI), and
provided inferior results. The high reactivity of the developed
catalyst system is highlighted in the Suzuki biaryl coupling of
24 unique substrate combinations to produce biaryls bearing
electronically-differentiated substitution on both the boronic
acid and the amide coupling component (Scheme 8, 4a-q).
Importantly, electron-neutral (4a, 4d, 4f, 4c’, 4h), electron-
rich (4e’, 4j, 4k) and even electron-deficient nucleophiles (4b,
4c, 4e, 4g, 4i, 4l) that are typically less reactive in transmetal-
lation32 are well-tolerated in this coupling. Furthermore, the
reaction is compatible with the synthesis of highly electron-
deficient poly-fluorinated biaryls (4l, 4g, 4i’, 4o-p) that have
widespread application in academic and industrial research.26
Importantly, ketone-containing substrates that are problematic
in the related Suzuki-Miyaura cross-coupling of esters18b are
well-tolerated (4c, 4c’, 4g, 4g’). The reaction is also compati-
ble with steric hindrance as demonstrated by the synthesis of
ortho-substituted biaryls from either the boronic acid (4m) or
amide component (4m’). Overall, the high efficiency and se-
lectivity of this reaction compares very well with the known
examples of the Suzuki biaryl coupling of amides and esters.
The superb selectivity for decarbonylation (>20:1 in all exam-
ples examined) bodes well for the general use of N-Ac-amides
in decarbonylative reactions of amides in lieu of aryl halides
and pseudohalides.3,24
Studies were conducted to gain insight into the mechanism
of the biaryl coupling and compare the reactivity with N-
glutarimides, thus far the only other type of amides to undergo
decarbonylative Suzuki coupling (Scheme 9). (1) Intermolecu-
lar competition experiments revealed that electron-deficient
arenes are inherently more reactive (4-CO2Me:4-Me = 86:14,
cf. glutarimide, 4-CO2Me:4-Me = 87:13), consistent with oxi-
dative insertion. (2) Furthermore, intermolecular competition
experiments revealed that the electronic nature of boronic acid
does not significantly affect the reactivity11b (4-t-Bu:4-CO2Me
= 56:44, cf. glutarimide, 4-4-t-Bu:4-CO2Me = 49:51). (3)
Moreover, sterically-demanding amides are less reactive than
their non-hindered counterparts (4-Me:2-Me = 78:22, cf. glu-
tarimide, 4-Me:2-Me = 21:79), while the steric hindrance on
boronic acid does not significantly affect the reactivity (4-
Me:2-Me = 54:46, cf. glutarimide, 4-Me:2-Me = 40:60). Col-
lectively, the studies provide strong support for amide bond
activation by oxidative insertion of Ni(0) into the N–C(O)
bond to afford acyl-Ni(II) intermediate. The high chemoselec-
tivity for the N–C(O) activation results from ground state de-
stabilization of the amide bond.9b The high selectivity for de-
carbonylative vs. acyl coupling suggests facile decarbonyla-
tion under the reaction conditions.
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To gain insight into the structural factors that control the
Page 6 of 9
significant twist of the amide bond provides strong support for
high chemoselectivity of the N–C(O) cleavage as a result of
ground state destabilization by rotation. Cleavage of the alter-
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high reactivity of N-Ac-amides, the X-ray structure of 1a was
determined (Figure 3). Remarkably, the amide shows approx-
imately half-twisted amide bond ( = 43.0°, N = 10.9°, C =
3.4°). The N–C(O) and C=O bond lengths are 1.422 Å and
1.213 Å. In contrast, the N-Ac bond is virtually planar;
native N-Ac bond is disfavored due to nN→*
conjugation,
C=O
as expected for a typical planar amide.10 The unique activity of
N-Ac amides can thus be explained by classical amidic reso-
nance, whereby the diminution of the resonance is achieved by
resonance and steric effects.
Next, we conducted computational studies to determine the
effect of N-Ac substitution on amide bond destabilization
(Scheme 10 and SI). (1) Resonance energy (RE) determined
by the COSNAR method8b show that (i) amidic resonance in
1a (RE = 8.4 kcal/mol) is lower than in the planar amides, and
this value is within the range for metal insertion under mild,
chemoselective conditions;29a (ii) RE of the N-Ac group (RE =
10.7 kcal/mol) confirms the energetic preference for activation
of the twisted amide bond. (2) Rotational profile of 1a was
determined by systematic rotation along the O–C–N–C(Ar)
dihedral angle (Figure 4), and it identified the energy mini-
mum at ca. 40° O–C–N–C angle ( = 33.15°; N = 14.92°) in a
syn O–C–N–C(Me) conformation (ca. 25.1° O–C–N–C(Me) dihe-
dral angle). The energy maximum is located at ca.180° O–C–
N–C dihedral angle ( = 12.62°; N = 15.96°) in an antiperi-
planar O–C–N–C(Me) destabilizing conformation (ca. 164.0°
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Figure 3. (a) Crystal structure of 1a. (b) Newman projection along the N–
C(O) bond (PhCO–, top; Ac–, bottom). Bond lengths (Å) and angles
(deg): N1–C1, 1.422(2); C1–O1, 1.213(2); C9–C1, 1.479(2); N1–C2,
1.395(2); C2–O2, 1.209(2), C15–C2, 1.509(2); C9–C1–N1–C2, –140.8(2);
O1–C1–N1–C3, –133.3(2); O1–C1–N1–C2, 35.8(2); C9–C1–N1–C3,
50.1(2); C15–C2–N1–C3, –179.3(1); O2–C2–N1–C1, –170.6(1); O2–C2–
N1–C3, –1.5(2); C15–C2–N1–C1, 11.6(2). Note much weaker N1–C1(O)
than N1–C2(O) bond.
Scheme 9. Competition Experiments
Scheme 10. A) Effect of Acyl Group; B) Graphical Repre-
sentation of Acyl-Twisting Destabilization Mechanisma
aNote a gradual increase of RE by changing a single N-substituent at the
nitrogen atom. RE of MeCONMe2 = 18.3 kcal/mol.11
Plot of Energy vs. O−C−N−C Dihedral Angle (1a)
PhCO
Ac
7
6
5
4
3
2
1
0
-150
-100
-50
0
50
100
150
O−C−N−C []
( = 5.1°, N = 10.9°, C = 2.2°). The N–C(O) and C=O bond
lengths of 1.395 Å and 1.209 Å in the N-Ac moiety further
indicate a more pronounced resonance stabilization of the N-
Ac amide bond. The N-Ac C=O bond in 1a is antiperiplanar to
the N–C(O) bond (170.6°), while the C–Me bond is antiperi-
planar to the N–Ar bond (179.3°). While compared with the
amide bond distortion in N-benzoyl-glutarimide9b ( = 87.5°,
N = 5.6°, C = 1.3°; N–C(O) = 1.475 Å, C=O = 1.200 Å),
these values indicate less pronounced destabilization in 1a, the
Figure 4. Rotational profile (1a, E, kcal/mol, vs. O–C–N–C [°]). PhCO
(red) indicates rotation along the PhCO–N axis; Ac (blue) indicates rota-
tion along the Ac–N axis. Rotational profile including planar DMAc
(N,N-dimethylacetamide, E = 19.51 kcal/mol) is shown in the Support-
ing Information.
O–C–N–C(Me) dihedral angle). In contrast, systematic rotation
along the O–C–N–C(Ar) dihedral angle for the Ac group (Fig-
ure 4) reveals the energy minimum at ca. 0° O–C–N–C angle
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( = 9.35°; N = 15.07°), while the energy maximum is located
ACKNOWLEDGMENT
1
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3
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5
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7
8
at ca. 80° O–C–N–C dihedral angle ( = 85.93°; N = 12.91°),
as expected for planar amides.10 Thus, rotational profiles pro-
vide further evidence for the chemoselective N–C(O) cross-
coupling in N-Ac amides. (3) Determination of N-/O-
protonation affinities (PA) in 1a indicates that this amide
strongly favors protonation at the amide oxygen atom (PA =
15.8 kcal/mol, the planar N-Ac amide bond). Interestingly,
protonation at the oxygen of the N-Ac group is strongly fa-
vored over the O-protonation of the twisted amide bond (PA
= 10.9 kcal/mol, the twisted amide). Thus, O-protonation of
the N-Ac group is an additional factor activating the N–C(O)
twisted amide bond33 towards selective scission due to en-
hanced Nlp conjugation.
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The Bruker 500 MHz spec-
trometer used in this study was supported by the NSF-MRI grant
(CHE-1229030). We thank the Wroclaw Center for Networking
and Supercomputing (grant number WCSS159).
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Collectively, the structural and energetic parameters deter-
mined for the amide bond in 1a indicate amide twist and elec-
tronic destabilization imposed by the amide framework as
empowering features for N–C(O) activation, thus providing
the basis for chemoselective utilization of N-Ac amides in a
wide range of cross-coupling protocols by acyl- and decar-
bonylative pathways.
In conclusion, we have reported the first Pd-catalyzed acyl
and Ni-catalyzed decarbonylative Suzuki-Miyaura cross-
coupling of N-acetyl-amides with arylboronic acids. The
methods developed here represent divergent approaches to the
widespread utilization of common acyclic amides in organic
chemistry. Most crucially, this report introduces N-acetyl-
amides as the most reactive acyclic amides developed thus far
in the burgeoning manifold of transition-metal-catalyzed am-
ide cross-coupling. The methods allow for a rapid access to a
variety of biaryl ketones and biaryls from easily accessible
acyclic amides with exceptional coupling selectivity. The high
reactivity of N-Ac-amides allowed for the first example of the
biaryl Suzuki-Miyaura cross-coupling of simple acyclic am-
ides.34 These biaryl products represent some of the most im-
portant building blocks in organic chemistry. Mechanistic and
structural interrogations provided evidence for re-modeling of
amidic resonance and amide bond twist as selectivity deter-
mining features in the cross-coupling of amides. We fully ex-
pect that knowledge gained in this study will inspire the de-
velopment of new synthetic methods. We anticipate N-Ac-
amides to be exploited as generic precursors in amide bond
cross-coupling enabling previously inaccessible reactivity of
the amide bond. Future studies will be aimed at investigating
new amide electrophiles for cross-coupling.
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ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization data, CIF file for amide 1a,
computational details. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
michal.szostak@rutgers.edu
§These authors contributed equally to this work.
(9) For pertinent studies on amide destabilization in N–C cross-
coupling, see: (a) Szostak, R.; Shi, S.; Meng, G.; Lalancette, R.; Szos-
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(Boc) and N-Acyl-tosylamides (Ts): Twisted Amides of Relevance to
Notes
The authors declare no competing financial interest.
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