N-Acyl-glutarimides: Effect of Glutarimide Ring on the Structures of Fully Perpendicular Twisted Amides and N-C Bond Cross-Coupling

Article abstract of DOI:10.1021/acs.joc.0c00227

N-Acyl-glutarimides have emerged as the most reactive precursors for N-C(O) bond cross-coupling reactions to date, wherein the reactivity is driven by ground-state destabilization of the amide bond. Herein, we report a full study on the effect of a glutarimide ring on the structures, electronic properties, and reactivity of fully perpendicular N-acyl-glutarimide amides. Most notably, this report demonstrates the generality of deploying N-acyl-glutarimides to achieve full twist of the acyclic amide bond, and results in the discovery of N-acyl-glutarimide amide with an almost perfect twist value, τ = 89.1°. X-ray structures of five new N-acyl-glutarimides are reported. Reactivity studies in the Suzuki-Miyaura cross-coupling and transamidation reactions provide insight into the reactivity of N-acyl-glutarimides in metal-catalyzed and transition-metal-free reactions. The effect of distortion, structures, and rotational barriers around the N-C(O) axis is discussed. The ability to achieve full distortion of the amide bond significantly expands the range of reagents available for N-C(O) cross-coupling reactions.

Full text of DOI:10.1021/acs.joc.0c00227

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Article
N-Acyl-Glutarimides: Effect of Glutarimide Ring on the Structures of
Fully Perpendicular Twisted Amides and N–C Bond Cross-Coupling
Md. Mahbubur Rahman, Chengwei Liu, Elwira Bisz, B#a#ej Dziuk, Roger
A Lalancette, Qi Wang, Hao Chen, Roman Szostak, and Michal Szostak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00227 • Publication Date (Web): 11 Mar 2020
Downloaded from pubs.acs.org on March 13, 2020
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The Journal of Organic Chemistry
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N-Acyl-Glutarimides: Effect of Glutarimide Ring on the
Structures of Fully Perpendicular Twisted Amides and
N–C Bond Cross-Coupling
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Md. Mahbubur Rahman,† Chengwei Liu,† Elwira Bisz,‡ Błażej Dziuk,‡,|| Roger Lalancette,† Qi Wang,¶
Hao Chen,¶ Roman Szostak,§ and Michal Szostak*,†
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United
States
‡Department of Chemistry, Opole University, 48 Oleska Street, Opole 45-052, Poland
||Department of Chemistry, Wroclaw University of Science and Technology, Norwida 4/6 14, Wroclaw
50-373, Poland
¶Department of Chemistry & Environmental Science, New Jersey Institute of Technology, Newark, NJ
07102, USA
§Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
Corresponding author
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michal.szostak@rutgers.edu
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Abstract
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`
N-Acyl-glutarimides have emerged as the most reactive precursors for N–C(O) bond cross-coupling
reactions to date, wherein the reactivity is driven by ground-state-destabilization of the amide bond.
Herein, we report a full study on the effect of glutarimide ring on the structures, electronic properties
and reactivity of fully perpendicular N-acyl-glutarimide amides. Most notably, this report demonstrates
the generality of deploying N-acyl-glutarimides to achieve full twist of the acyclic amide bond, and
results in the discovery of N-acyl-glutarimide amide with an almost perfect twist value,  = 89.1°. X-ray
structures of five new N-acyl-glutarimides are reported. Reactivity studies in the Suzuki–Miyaura cross-
coupling and transamidation reactions provide insight into the reactivity of N-acyl-glutarimides in
metal-catalyzed and transition-metal-free reactions. The effect of distortion, structures and rotational
barrier around the N–C(O) axis is discussed. The ability to achieve full distortion of the amide bond
significantly expands the range of reagents available for N–C(O) cross-coupling reactions.
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The Journal of Organic Chemistry
1. Introduction
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The utility of amides in various areas of chemical science has spurred intense research on the
discovery of cross-coupling reactions by N–C(O) bond cleavage.1–3 In this regard, N-acyl-glutarimides
discovered by our laboratory in 2015 have become the reagents of choice for the development and
optimization of new cross-coupling reactions by N–C(O) bond activation (Figure 1).4–6 A common
element for all successful amide precursors developed to date for cross-coupling reactions is ground-
state-destabilization of the amide bond, which permits for highly selective oxidative addition of the N–
C(O) bond to form a stable acyl-metal complex,7 despite the traditional high amidic resonance of planar
amide bonds (nN → *C=O conjugation, 15-20 kcal/mol in planar amides).8–17
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Figure 1. (a) Amide N–C bond activation. (b) N-Acyl-glutarimides: the most reactive and versatile
amides in N–C bond cross-coupling.
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Given that NH-glutarimides are cheap, commercially available or readily synthesized from the
corresponding glutaric acids,18 and thus far represent the only class of amide precursors that have
enabled close to full distortion of the amide bond that translates to the development of a wide range of
synthetically useful cross-coupling reactions,3–6 expanding the toolbox of N-acyl-glutarimides is
extremely attractive. Herein, we report a full study on the effect of glutarimide ring on the structures,
electronic properties and reactivity of fully perpendicular N-acyl-glutarimides. Most notably, this study
demonstrates the generality of deploying N-acyl-glutarimides to achieve full twist of the acyclic amide
bond, resulting in the discovery of N-acyl-glutarimide with an almost perfect twist value,  = 89.1°. X-
ray structures of five new N-acyl-glutarimides are reported. Reactivity studies in the Suzuki–Miyaura
cross-coupling and transamidation reactions provide insight into the reactivity of N-acyl-glutarimides in
metal-catalyzed and transition-metal-free reactions. The effect of distortion, structures and rotational
barrier around the N–C(O) axis is discussed. Collectively, the ability to achieve full distortion of the
amide bond significantly expands the range of reagents available for N–C(O) cross-coupling reactions.
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2. Results and Discussion
The planarity of the amide bond is a fundamental property of amides described in all organic
chemistry textbooks.1,2 While in classical amides coplanarity of the six atoms comprising the amide
bond results in low reactivity of amide linkages,8,9 geometrical distortion of the amide bond from
planarity brings about significantly enhanced reactive properties of amides.10–17 Conventionally,
distortion of the amide bond from planarity has been achieved by placing the nitrogen atom in a rigid
bicyclic ring system.10,17b In recent years, geometric distortion of acyclic amides has emerged as an
effective way to commonly employ these twisted amides in cross-coupling reactions.19 To date, only N-
acyl-glutarimide amides have come close to achieving the full distortion of the amide bond,7a rendering
them the reagents of choice for cross-coupling reactions. To expand the range of N-acyl-glutarimide
amides available for cross-coupling reactions to the broad synthetic community, we conducted a study
of the effect of N-glutarimide ring on the structure, electronic and reactive properties of N-acyl-
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The Journal of Organic Chemistry
glutarimides. N-Acyl-glutarimides have been selected for this study due to much higher reactivity in N–
C(O) cross-coupling reactions than N-acyl-succinimides,4–6 which is related to the higher twist angle of
N-acyl-glutarimides.7 It is also worth noting that di-substituted glutarimides are readily available from
the corresponding glutaric acids by one-pot amidation/cyclization,18 which should facilitate fine-tuning
of N-acyl-glutarimides for N–C(O) cross-couplings, including by decarbonylative pathways. More
broadly, N-acyl-glutarimides can be regarded as “not additionally stabilized” amides. N-Acylation and
related types of Nlp delocalization exert a substantial effect on the electronic properties of amides.
Studies are ongoing to provide a comprehensive survey of changes in amidic resonance in commonly
used amides and derivatives, wherein it appears that triacyl derivatives, such as N-acyl-glutarimides
represent an extreme case of non-stabilized, perfectly twisted, yet stable amide derivatives.7a–b
Crystallographic Studies. The structures of N-acyl-glutarimides (1–6) selected for the study are
shown in Figure 2. The parent N-benzoyl-glutarimide (1) has been previously reported by us, and
represents the only compound in this class developed to date.4–7 All N-acyl-glutarimides were
synthesized in 78-96% yields on gram scale from the corresponding acyl chlorides (see the Supporting
Information) and purified by chromatography or recrystallization. All N-acyl-glutarimides 1–6 are
stable solids, with no decomposition observed after bench-top storage for periods of >6 months without
taking any precautions to exclude air or moisture. The amides selected for this study include geminally-
substituted 3,3-dimethyl glutarimide (2), 3,3-tetramethylene glutarimide (3), 3,3-pentamethylene
glutarimide (4), biologically-relevant 3-phenyl glutarimide (5)20 and 1,8-napthalimide (6) that is a
common precursor to perylene dyes and DNA targeting agents.21
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Figure 2. Structures of N-acyl-glutarimides used in this study.
We initiated our study by obtaining X-ray structures of all N-acyl-glutarimides (1–6). Samples
suitable for X-ray analysis were obtained by slow evaporation from CH2Cl2. Crystal data and structure
refinement summaries for 2-6 are included in the SI, Tables S1-S2. The X-ray structure of the parent
amide 1 has been previously reported.7a The Winkler-Dunitz distortion parameters (, N), the additive
distortion parameter (+N), and selected bond lengths of amides 1–6 are summarized in Table 1. For
comparison, Table 1 also includes fully perpendicular model bridged lactam, 2-quinuclidonium
tetrafluoroborate, and planar formamide.
The structures of amides 1–6 are presented in Figure 3 together with their Newman projections along
the N–C(O) bonds. All structures have been deposited with the Cambridge Crystallographic Data Center
as supplementary publication No. 1969082 (2), 1969086 (3), 1969087 (4), 1969085 (5), 1969088 (6).
The expanded ORTEP structures of amides 1–6 are presented in the Supporting Information.
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Figure 3. Structures of N-acyl-glutarimides used in this study. Crystal structures of (a) 1,7a (b) 2, (c) 3,
(d) 4, (e) 5, and (f) 6. (50% ellipsoids). Insets show Newman projections along the N–C(O) axis. See SI
for expanded ORTEP structures. See, Table 1 for bond lengths (Å) and Winkler-Dunitz distortion
parameters (deg). CCDC 1969082 (2), 1969086 (3), 1969087 (4), 1969085 (5), 1969088 (6). (Please,
use double column format for Figure 3)
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Most interestingly, the X-ray structures of N-acyl-glutarimides 1–6 demonstrate that these compounds
are among the most twisted amides structurally characterized to date, with twist angles () ranging from
77.7° to 89.1°. Remarkably, the 3,3-tetramethylene derivative (3) is characterized by the most twisted
acyclic amide bond in this series crystallized to date ( = 89.1°; cf. parent N-benzoyl-glutarimide,  =
87.5°).7a In contrast, the nitrogen atom remains practically planar, with (N) ranging from 5.6° to 8.7°.
Thus, these compounds are categorized as classic twisted amides according to the Yamada
classification.15
The N–C(O) bond length varies from 1.455 Å (3) to 1.475 Å (1 and 2), while the C=O bond length is
between 1.186 Å (4) and 1.218 Å (2). There appears to be no clear correlation involving Winkler-Dunitz
parameters and bond lengths, likely due to their placement at the extreme maximum of the amide bond
distortion. It is useful to compare (i) the N–C(O) bond lengths in neutral 1–6 (average of 1.467 Å) with
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the N-protonated 2-quinuclidonium tetrafluoroborate (1.524 Å) and formamide (1.349 Å), and (ii) the
C=O bond lengths in 1–6 (average of 1.199 Å) with the N-protonated 2-quinuclidonium
tetrafluoroborate (1.192 Å) and planar formamide (1.193 Å). The order of distortion based on the X-ray
data in the series 1–6 is as follows: 3 > 2 > 1 > 6 > 5 > 4, with the maximum additive distortion
parameter11d (+N) of 96.1° reached by amide 3 (vide infra). Interestingly, the C3-geminal
substitution does not have a major effect on the N-acyl amide bond distortion (eclipsed C=O/C3–Me
conformation, transannular distance between C3–Me hydrogen and C=O of 3.554 Å).
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Table 1. Selected Crystallographic Structural Parameters of N-Acyl-Glutarimides 1–6 and
Representative Amidesa
N–C(O)
[Å]
C=O
[Å]
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N
[deg]
+N
[deg]
entry
amide
[deg]
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3b
4b
5b
6b
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1.476
1.475
1.455
1.459
1.467
1.473
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1.192
1.196
87.48
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85.95
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96.10
86.41
90.26
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2-
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8d
quinuclidonium
tetrafluoroborate
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1.192
89.12
59.475
0.0
148.60
0.0
formamide
1.349
1.193
0.0
aRef. 7a. bThis study. X-ray structures. cRef. 10a. dCalculated values. Ref. 11a.
Reactivity Studies. Having established the extreme distortion of amides in the series 1–6, we were
keen to examine their reactivity in the model Suzuki–Miyaura cross-coupling reaction (Table 2). We
selected conditions catalyzed by [Pd(IPr)(cin)Cl] (cin = cinnamyl, IPr = 1,3-bis(2,6-
diisopropylphenyl)imidazo-2-ylidene)3a,22 because of the beneficial properties of the well-defined
Pd(II)–NHC precatalysts and well-established catalytic cycle.
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As summarized in Table 2, the model Suzuki–Miyaura cross-coupling using 4-tolylboronic acid
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proceeded in excellent yields with all compounds 1–6 at 3 mol% (conditions A) and 1 mol% (conditions
B) catalyst loading (quantitative conversions). Furthermore, decreasing the catalyst loading to 0.10
mol% (conditions C) resulted in uniformly high TON (TON = turnover number) of 820-860 with all
amides 1–6, while a further decrease in catalyst loading to 0.05 mol% (conditions D) gave 31-38%
conversions with all compounds 1–6. Moreover, we tested the aqueous conditions at 1.0 mol% catalyst
loading (conditions E). Interestingly, under these conditions we found that N-acyl-glutarimides 3 (85%)
and 4 (72%) are more reactive than amides 1 (56%) and 2 (61%) and significantly more reactive than
amides containing aromatic rings in the glutarimide part, 5 (27%) and 6 (45%). Thus, the Suzuki–
Miyaura cross-coupling with amides 1–6 established (i) excellent reactivity of 1–6 under the model
reaction conditions (conditions A–D), and (ii) demonstrated that amides 1–6 show significant variations
under aqueous conditions (conditions E), which is likely due to lower solubility of the less reactive
amides in the solvent system.
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To gain further insight into the reactivity of fully twisted amides 1–6 in the Suzuki–Miyaura cross-
coupling, we conducted kinetic studies (Table 3 and Figure 4). For this study we employed non-aqueous
conditions at 1.0 mol% catalyst loading. Interestingly, we found that while amides 1–5 showed similar
reaction kinetics with full conversion observed after approximately 20 min, the naphthalene derivative 6
was significantly slower to react, reaching full conversion after approximately 60 min. Thus, a
difference in reactivity resulting from variations in solubility is an important parameter to keep in mind
when optimizing cross-coupling reactions with N-acyl-glutarimides. In particular, the slow release of
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Table 2. Effect of Glutarimide Ring on Suzuki–Miyaura Cross-Coupling by N–C Bond Cleavagea
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conditions (%)
entry
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amide
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B
C
D
E
>98
>98
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3
>98
>98
>98
>98
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>98
>98
>98
>98
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>98
>98
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aConditions: amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd] (x mol%), K2CO3 (3.0 equiv), THF (0.25
M), 60 °C, 15 h. Conditions A: [Pd] (3 mol%). Conditions B: [Pd] (1.0 mol%). Conditions C: [Pd] (0.10
mol%). Conditions D: [Pd] (0.05 mol%)). Conditions E: [Pd] (1.0 mol%), H2O (5 equiv), RT. Neolyst
CX31 = [Pd(IPr)(cin)Cl].
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Table 3. Reactivity of N-Acyl-glutarimides 1-6 in Suzuki–Miyaura Cross-Couplinga
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time (min)
entry
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amide
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60
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92
>98
>98
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>98
>98
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>98
>98
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>98
aConditions: amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd] (1.0 mol%), K2CO3 (3.0 equiv), THF (0.25
M), 60 °C, 5-60 min. Percentage yield is shown.
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Figure 4. Kinetic profile of N-acyl-glutarimides 1-6 in Suzuki–Miyaura cross-coupling. Conditions:
amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd] (1.0 mol%), K2CO3 (3.0 equiv), THF (0.25 M), 60 °C, 5-
60 min.
amide 6 could be beneficial for cross-coupling reactions, especially in cases when small concentration
of the reagent is needed for optimal results.
The further probe the reactivity of amides 1–6 in the model Suzuki–Miyaura cross-coupling, we
conducted a comparative study using representative electron-rich, electron-withdrawing and sterically-
demanding boronic acids as the cross-coupling partners (Table 4). Pleasingly, we found that all amides
1–6 showed excellent reactivity using electron-rich boronic acids (4-tolylboronic acid and 4-
methoxyphenylboronic acid, quantitative conversions), while the reactions using challenging electron-
poor 4-trifluromethylphenylboronic acid (80-89%) and sterically-demanding 2-tolylboronic acid (97%-
quantitative) showed acceptable and excellent reactivity, respectively. Importantly, the cleavage of the
alternative N–C(O) bond of the glutarimide ring was not observed under any of the conditions, attesting
to the high capacity of amides 1–6 to serve as N–C(O) cleavage precursors in transition-metal-catalysis.
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Table 4. Reactivity of N-Acyl-glutarimides 1-6 in Suzuki–Miyaura Cross-Coupling with Various
1
2
3
Boronic Acidsa
4
5
6
7
8
9
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entry
amide
1
2
>98
>98
>98
>98
80
80
97
98
3
>98
>98
80
>98
4
5
>98
>98
>98
>98
82
82
97
98
6
>98
>98
89
>98
aConditions: amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd] (1.0 mol%), K2CO3 (3.0 equiv), THF
(0.25 M), 60 °C, 15 h. Percentage yield is shown. 7a: phenyl(p-tolyl)methanone; 7b: (4-
methoxyphenyl)(phenyl)methanone; 7c: phenyl(4-(trifluoromethyl)phenyl)methanone; 7d: phenyl(o-
tolyl)methanone.
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1
2
3
4
5
6
7
8
The influence of the glutarimide ring on transition-metal-free reactions was also examined (Table 5).23
We selected transamidation reactions under additive-free conditions as our model system because these
reactions represent arguably the most convenient method to perform transamidations24 to construct new
amide bonds under mild conditions. As shown in Table 5, all amides 1–6 showed excellent reactivity
using nucleophilic benzylamine (conditions A) and more challenging morpholine (conditions B),
resulting in quantitative conversions at room temperature in the absence of any additives. Moreover,
these reagents enable for the first time to use non-nucleophilic p-anisidine (conditions C-D) and
sterically-hindered tert-butylamine (conditions E-F) as nucleophiles. While in these more challenging
cases higher temperature is required for transamidation, it is very interesting to note that the new
reagents 2–6 show significantly higher reactivity than the parent N-benzoyl-glutarimide 1 (71-83% vs.
27%, conditions D, and 91-97% vs. 49%, conditions F). Thus, the new twisted amides 2–6 might find
applications not only in the transition-metal-catalysis but also in the emerging manifold of transition-
metal-free acyl activation reactions23 of the amide bond.
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Computational Studies. We also conducted computational studies to gain additional insight into the
structures and ground-state-destabilization of twisted N-acyl-glutarimides 1–6 (Tables 6-7 and Figure
5). B3LYP/6-311++G(d,p) level was selected to conduct geometry optimization because of good
reproducibility of literature data and method practicality. Most importantly, optimization of the
geometries of amides 1–6 clarifies the data obtained from the X-ray crystallography. It is well-
established that crystal packing and non-bonding interactions might impact structural parameters of the
amide bond, while a combined approach based on computational evaluation of crystallographically-
determined amides in a series of compounds provides a reliable pathway to elucidate ground-state-
destabilization of amides. Thus, the Winkler-Dunitz distortion parameters (, N), the additive distortion
parameter (+N), and selected bond lengths of amides 1–6 optimized at the B3LYP/6-311++G(d,p)
level are listed Table 6. We employed X-ray structures of amides 1–6 as the starting geometry and
performed full optimization. The computationally-determined structures of amides 1–6 are presented in
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Table 5. Reactivity of N-Acyl-glutarimides 1-6 in Transamidation Reactions with Various
Aminesa
1
2
3
4
5
6
7
8
9
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conditions (%)
entry
1
amide
A
B
C
D
E
F
>98
>98
<5
27
<5
49
2
3
>98
>98
>98
>98
<5
<5
83
73
<5
<5
95
92
4
5
>98
>98
>98
>98
7
71
74
<5
<5
95
91
<5
6
>98
>98
5
75
<5
97
aConditions: amide (1.0 equiv), amine (2.0 equiv), CH3CN (0.50 M), RT or 120 °C, 15 h. Conditions
A: benzylamine, RT. Conditions B: morpholine, RT. Conditions C: p-anisidine, RT. Conditions D: p-
anisidine, 120 °C Conditions E: tert-butylamine, RT. Conditions F: tert-butylamine, 120 °C. 8a: N-
benzylbenzamide; 8b: morpholino(phenyl)methanone; 8c: N-(4-methoxyphenyl)benzamide; 8d: N-
(tert-butyl)benzamide.
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Figure 5. Figure 5 also shows Newman projections along the N–C(O) bonds in the ground-state (blue
box) and Newman projections along the N–C(O) bonds at the maximum (red box) (Table 7, vide infra).
Interestingly, we found that the order of distortion for amides 1–6 determined by computations is as
follows: 4 > 2 > 3 > 1 = 5 > 6. Furthermore, computations demonstrate that the main difference in
distortion of amides 1–6 arises from nitrogen pyramidalization (N) ranging from 6.6° to 9.1°, while all
1
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amides 1–6 are practically perpendicular in gas phase: () ranging from 89.8° to 90.0°. While the
observed differences are relatively small, the observed trend is consistent with an increased nitrogen
pyramidalization (N) effected by electron-donating groups adjacent to the amide bond.19
Figure 5. Structures of (a) 1, (b) 2, (c) 3, (d) 4, (e) 5, and (f) 6 at the (B3LYP/6-311++G(d,p))) level.
Insets show Newman projections along the N–C(O) axis in the ground-state conformation (blue) and at
the O–C–N–C dihedral angle -10° (maximum). See Table 6 and Figure 6 for bond lengths (Å), Winkler-
Dunitz distortion parameters (deg) and energies (kcal/mol). (Please, use double column format for
Figure 5)
The parent N-benzoyl-glutarimide represents a rotationally-inverted amide with energy maximum
identified at -10° dihedral angle by a systematic rotation along the O–C–N–C dihedral angle.7a Thus, to
gain further insight into the rotational barriers of amides 1–6, we performed geometry optimization at
the energy maximum of amides 1–6. The data is shown in Table 7, while a graphical representation of
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Newman projections along the N–C(O) axis is shown in Figure 5 (red box). Interestingly, all N-acyl-
glutarimides 1–6 are characterized by very high barriers to rotation of 12-13 kcal/mol at ca. –10° O–C–
N–C angle, while the energy reaches minimum at ca. 90° O–C–N–C angle. The naphthalene derivative
6 shows the highest barrier to rotation around the N–C(O) axis (13.11 kcal/mol), while the rotational
barriers of amides 1–5 range from 11.77 kcal/mol (4) to 11.98 kcal/mol (5) (Figure 6). Overall, the high
barrier to rotation indicates a strong preference of amides 1–6 to remain in the ground-state twisted
conformation.24 This ground-state destabilization of bench-stable amides is the main factor responsible
for the high reactivity of acyclic twisted amides in chemoselective reactions involving activation of the
N–C(O) bond in transition-metal-catalysis and nucleophilic acyl addition reactions.
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2
3
4
5
6
7
8
9
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Table 6. Energies and Selected Structural Parameters of N-Acyl-Glutarimides 1–6 (B3LYP/6-
311++G(d,p)))a
N–C(O)
[Å]
C=O
[Å]

N
[deg]
+N
[deg]
entry amide
–ET [au]
[deg]
1
2
3
4
5
6
1
2
3
4
5
6
744.56085
823.21112
900.64228
939.97320
975.66608
1011.38316
1.493
1.491
1.491
1.491
1.493
1.492
1.198
1.198
1.198
1.198
1.198
1.198
90.00
90.00
89.82
89.83
90.00
90.00
7.25
8.99
8.33
9.08
7.22
6.56
97.25
98.99
98.15
98.91
97.22
96.56
aFor structures, see Figure 5.
Table 7. Energies of N-Acyl-Glutarimides 1-6 as Function of Dihedral Angle (E, kcal/mol vs. O–
C–N–C [°] (B3LYP/6-311++G(d,p)))a
E [kcal/mol]
entry
amide
-20°
-10°
0°
10°
20°
90°
1
2
3
4
5
1
2
3
4
5
6.794
6.709
6.476
4.743
6.646
11.928
11.840
11.816
11.772
11.981
10.741
10.788
10.777
10.700
10.677
8.491
9.043
8.986
8.882
8.413
6.370
6.650
6.597
6.516
6.292
0.018
0.022
0.025
0.017
0.018
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6
6
7.499
13.112
11.879
10.050
7.499
0.014
1
2
3
a1: E = 0 kcal/mol at 86.38° O–C–N–C; 2, 85.51° O–C–N–C; 3, 85.64° O–C–N–C; 4, 85.65° O–C–
4
5
N–C; 5, 86.38° O–C–N–C; 6, 86.72° O–C–N–C. See SI for details.
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Figure 6. Rotational barriers of amides 1-6 (kcal/mol). Note that the barriers represent energies required
to reach planarity by fully twisted N–C(O) bonds.
3. Conclusions
In summary, we have reported a full study on the effect of glutarimide ring on the structures,
reactivity and electronic properties of fully perpendicular N-acyl-glutarimide amides. We have
established the generality of the amide bond twist in the class of reagents that have been shown as the
most reactive in the powerful manifold of amide bond N–C(O) cross-coupling. This study reports the
most twisted N-acyl-glutarimide discovered to date with an almost perfect twist value determined
crystallographically,  = 89.1°. Examination of the reactivity of N-acyl-glutarimide amides in the model
Suzuki-Miyaura cross-coupling and transamidation reactions provided insight into the reactivity and
established new more reactive N-acyl-glutarimides for both classes of reactions. Computational studies
provided insight into the distortion and rotational barriers of N-acyl-glutarimides. Remarkably, these N-
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acyl-glutarimides are uniformly characterized by extremely high barriers to rotation (E = approx. 12-
13 kcal/mol) in rotationally-inverted scaffolds (energy minimum at 90°). The capacity to fully twist the
amide bond in a wide range of N-acyl-glutarimides significantly expands the access to novel reagents
for the development of new N–C(O) bond activation reactions.
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Experimental Section
General Methods. All compounds reported in the manuscript have been previously described in
literature or prepared by the method reported previously unless stated otherwise. All experiments
involving palladium were performed using standard Schlenk techniques under nitrogen or argon unless
stated otherwise. All solvents were purchased at the highest commercial grade and used as received or
after purification by distillation from sodium/benzophenone under nitrogen. All solvents were
deoxygenated prior to use. All other chemicals were purchased at the highest commercial grade and
used as received. All other general methods have been published.4a-b 1H NMR and C NMR data are
13
1
13
given for all compounds in the Supporting Experimental for characterization purposes. H NMR, C
NMR and HRMS data are reported for all new compounds.
General Procedure for the Synthesis of N-Acyl-Glutarimides. Previously published procedure was
followed.4a-b An oven-dried round-bottomed flask equipped with a stir bar was charged with an amine
substrate (typically, 1.0-10.0 mmol, 1.0 equiv), 4-(dimethylamino)pyridine (typically, 0.10 equiv)
triethylamine (typically, 2.0 equiv), and dichloromethane (typically, 0.25 M). Benzoyl chloride
(typically, 1.5 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the
reaction mixture was stirred for 15 h at room temperature. After the indicated time, the reaction mixture
was washed with quenched with HCl (aq, 1.0 N, 1 x 20 mL), extracted with dichloromethane (2 x 20
mL), the organic layers were combined dried and concentrated. Purification by chromatography on
silica gel (hexanes/ethyl acetate = 1:1) or recrystallization (toluene) afforded the title products.
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Amide 1 has been previously reported in the literature.4a Spectroscopic properties matched literature
data. Amides 2, 3, 4, 5 and 6 are new compounds. All amides were fully characterized by X-ray
crystallographic analysis. Note: In our experience N-acyl-glutarimides are bench-stable, easy to purify
solids. We have not noticed any decomposition when storing at the bench-top over the course of >6
months.
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1-Benzoylpiperidine-2,6-dione (1). Yield 84% (1.10 g). (Hexanes/ethyl acetate = 1:1). White solid. 1H
NMR (500 MHz, CDCl3) δ 7.90 – 7.81 (m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 2.74
13
(t, J = 6.6 Hz, 4H), 2.10 (quint, J = 6.6 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 172.3, 171.1,
135.3, 132.0, 130.4, 129.4, 32.6, 17.7.
1-Benzoyl-4,4-dimethylpiperidine-2,6-dione (2). Yield 86% (1.27 g). (Hexanes/ethyl acetate = 1:1).
1
White solid. Mp = 155 – 156 °C. H NMR (500 MHz, CDCl3) δ 7.91 – 7.83 (m, 2H), 7.63 (t, J = 7.4
Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 2.62 (s, 4H), 1.24 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 171.8,
171.2, 135.2, 132.4, 130.5, 129.4, 46.3, 30.3, 28.3. HRMS (ESI) m/z: [M + H]+ Calcd for C14H16NO3
246.1125; Found 246.1124.
8-Benzoyl-8-azaspiro[4.5]decane-7,9-dione (3). Yield 94% (1.52 g). (Hexanes/ethyl acetate = 1:1).
1
White solid. Mp = 139 – 140 °C. H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 8.3, 1.1 Hz, 2H), 7.66 –
7.61 (m, 1H), 7.49 (t, J = 7.8 Hz, 2H), 2.71 (s, 4H), 1.82 – 1.76 (m, 4H), 1.70 – 1.67 (m, 4H). 13C{1H}
NMR (125 MHz, CDCl3) δ 172.0, 171.2, 135.2, 132.3, 130.5, 129.4, 44.9, 40.6, 38.3, 24.7. HRMS
(ESI) m/z: [M + H]+ calcd for C16H18NO3 272.1281; Found 272.1280.
3-Benzoyl-3-azaspiro[5.5]undecane-2,4-dione (4). Yield 96% (1.10 g). (Hexanes/ethyl acetate = 1:1).
1
White solid. Mp = 175 – 176 °C. H NMR (500 MHz, CDCl3) δ 7.90 – 7.83 (m, 2H), 7.64 (t, J = 7.4
13
Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 2.68 (s, 4H), 1.57 (s, 8H), 1.49 (s, 2H). C{1H} NMR (125 MHz,
CDCl3) δ 171.8, 171.2, 135.2, 132.4, 130.6, 129.4, 44.2, 36.7, 33.2, 25.9, 21.8. HRMS (ESI) m/z: [M +
H]+ Calcd for C17H20NO3 286.1438; Found 286.1436.
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1-Benzoyl-4-phenylpiperidine-2,6-dione (5). Yield 82% (1.46 g). (Hexanes/ethyl acetate = 1:1).
1
2
3
1
White solid. Mp = 117 – 118 °C. H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 2H), 7.63 (t, J =
4
5
6
7
8
9
7.4 Hz, 1H), 7.49 – 7.40 (m, 4H), 7.35 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 7.4 Hz, 2H), 3.65 – 3.57 (m, 1H),
3.11 – 2.97 (m, 4H). 13C{1H} NMR (125 MHz, CDCl3) δ 171.4, 170.8, 140.2, 135.3, 132.0, 130.6,
129.6, 129.4, 128.2, 126.8, 39.7, 35.2. HRMS (ESI) m/z: [M + H]+ Calcd for C18H16NO3 294.1125;
Found 294.1123.
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2-Benzoyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (6). Yield 78% (2.38 g). (Hexanes/ethyl acetate =
1:1). Red solid. Mp = 228 – 229 °C. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J = 7.2 Hz, 2H), 8.32 (d, J
= 8.2 Hz, 2H), 8.03 (d, J = 7.5 Hz, 2H), 7.81 (t, J = 7.7 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.8
13
Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 170.8, 163.9, 135.4, 135.3, 132.4, 132.2, 132.0, 130.8,
129.5, 129.2, 127.5, 122.4. HRMS (ESI) m/z: [M + H]+ Calcd for C19H12NO3 302.0812; Found
302.0810.
General Procedure for the Suzuki-Miyaura Cross-Coupling. An oven-dried vial equipped with a stir
bar was charged with an amide substrate (neat, 1.0 equiv), potassium carbonate (typically, 3.0 equiv),
boronic acid (typically, 2.0 equiv), Pd-NHC precatalyst (typically, 3 mol%), placed under a positive
pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. THF
(typically, 0.25 M) was added with vigorous stirring at room temperature, the reaction mixture was
placed in a preheated oil bath at 60 °C and stirred for the indicated time. After the indicated time, the
reaction mixture was cooled down to room temperature, diluted with CH2Cl2 (10 mL), filtered, and
1
concentrated. A sample was analyzed by H NMR (CDCl3, 500 MHz) and/or GC-MS to obtain
conversion, selectivity and yield using internal standard and comparison with authentic samples.
Analytical sample was purified by chromatography on silica gel (hexanes/ethyl acetate = 1:1) for
characterization purposes.
General Procedure for the Suzuki-Miyaura Cross-Coupling at Different Catalyst Loading. An
oven-dried vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv),
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potassium carbonate (3.0 equiv), boronic acid (2.0 equiv), [Pd(IPr)(cin)Cl] (x mol%), placed under a
positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum.
THF (0.25 M) was added with vigorous stirring at room temperature, the reaction mixture was placed in
a preheated oil bath at 60 °C and stirred for the indicated time. After the indicated time, the reaction
mixture was cooled down to room temperature, diluted with CH2Cl2 (10 mL), filtered, and concentrated.
A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and/or GC-MS to obtain conversion, selectivity
and yield using internal standard and comparison with authentic samples. Analytical sample was
purified by chromatography on silica gel (hexanes/ethyl acetate = 1:1) for characterization purposes.
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General Procedure for the Suzuki-Miyaura Cross-Coupling at Different Reaction Time. An oven-
dried vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv), potassium
carbonate (3.0 equiv), boronic acid (2.0 equiv), [Pd(IPr)(cin)Cl] (1 mol%), placed under a positive
pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. THF (0.25
M) was added with vigorous stirring at room temperature, the reaction mixture was placed in a
preheated oil bath at 60 °C and stirred for the indicated time. After the indicated time, the reaction
mixture was cooled down to room temperature, diluted with CH2Cl2 (10 mL), filtered, and concentrated.
A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and/or GC-MS to obtain conversion, selectivity
and yield using internal standard and comparison with authentic samples. Analytical sample was
purified by chromatography on silica gel (hexanes/ethyl acetate = 1:1) for characterization purposes.
General Procedure for the Suzuki-Miyaura Cross-Coupling with Different Boronic Acids. An
oven-dried vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv),
potassium carbonate (3.0 equiv), boronic acid (2.0 equiv), [Pd(IPr)(cin)Cl] (1 mol%), placed under a
positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum.
THF (0.25 M) was added with vigorous stirring at room temperature, the reaction mixture was placed in
a preheated oil bath at 60 °C and stirred for the indicated time. After the indicated time, the reaction
mixture was cooled down to room temperature, diluted with CH2Cl2 (10 mL), filtered, and concentrated.
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A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and/or GC-MS to obtain conversion, selectivity
and yield using internal standard and comparison with authentic samples. Analytical sample was
purified by chromatography on silica gel (hexanes/ethyl acetate = 1:1) for characterization purposes.
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General Procedure for Transamidation Reactions. An oven-dried vial equipped with a stir bar was
charged with an amide substrate (neat, 1.0 equiv), CH3CN (typically, 0.50 M) and amine (typically, 2.0
equiv) with vigorous stirring at room temperature. The reaction mixture was stirred at the indicated
temperature for 15 h. After the indicated time, the reaction mixture was diluted with EtOAc (10 mL),
washed with aqueous HCl (aq., 0.50 N, 5 mL), the aqueous layer was extracted with EtOAc (2 x 5 mL),
the organic layers were combined, dried, filtered, and concentrated. A sample was analyzed by 1H NMR
(CDCl3, 500 MHz) and/or GC-MS to obtain conversion, selectivity and yield using internal standard and
comparison with authentic samples. Analytical sample was purified by chromatography on silica gel
(hexanes/ethyl acetate = 1:1) for characterization purposes.
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Characterization Data of Cross-Coupling and Transamidation Products. All products reported in
this manuscript have been previously reported: 7a,4a 7b,4a 7c,4a 7d,4a 8a,26 8b,26 8c,26 8d.26
Spectroscopic data matched those reported in the literature. Compounds 7a, 7b, 7c, 7d, 8a, 8c, 8d have
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been quantified by H NMR spectroscopy (500 MHz) using nitromethane as internal standard.
Analytical samples were isolated for characterization purposes.
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Phenyl(p-tolyl)methanone (7a). (Hexanes/ethyl acetate = 10:1). White solid. H NMR (500 MHz,
CDCl3) δ 7.83 – 7.75 (m, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H),
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7.28 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ 196.8, 143.5, 138.3, 135.2,
132.5, 130.6, 130.2, 129.3, 128.5, 21.9.
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(4-Methoxyphenyl)(phenyl)methanone (7b). (Hexanes/ethyl acetate = 1:10). White solid. H NMR
(500 MHz, CDCl3) δ 7.85 – 7.79 (m, 2H), 7.78 – 7.71 (m, 2H), 7.58 – 7.52 (m, 1H), 7.46 (t, J = 7.6 Hz,
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2H), 6.98 – 6.93 (m, 2H), 3.87 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 195.8, 163.5, 138.6, 132.8,
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132.2, 130.4, 130.0, 128.5, 113.8, 55.8.
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Phenyl(4-(trifluoromethyl)phenyl)methanone (7c). (Hexanes/ethyl acetate = 10:1). White solid. H
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NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 2H), 7.80 (dd, J = 8.0, 0.9 Hz, 2H), 7.75 (d, J = 8.1 Hz,
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2H), 7.65 – 7.60 (m, 1H), 7.51 (t, J = 7.7 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 195.8, 141.1,
137.1, 134.1 (q, J = 32.8 Hz), 133.4, 130.5, 130.4, 128.9, 125.7 (q, J = 3.7 Hz), 124.0 (q, J = 273.13
Hz). 19F NMR (471 MHz, CDCl3) δ -63.01.
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Phenyl(o-tolyl)methanone (7d). (Hexanes/ethyl acetate = 10:1). Colorless oil. H NMR (500 MHz,
CDCl3) δ 7.85 – 7.76 (m, 2H), 7.61 – 7.56 (m, 1H), 7.46 (t, J = 7.5, 2H), 7.40 (td, J = 7.5, 1.3 Hz, 1H),
7.31 (dd, J = 11.8, 7.1 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 2.34 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3)
δ 198.9, 138.9, 138.1, 137.0, 133.4, 131.3, 130.5, 130.4, 128.8, 128.8, 125.5, 20.3.
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N-Benzylbenzamide (8a). (Hexanes/ethyl acetate = 4:1). White solid. H NMR (500 MHz, CDCl3) δ
7.79 (d, J = 7.7 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 4.3 Hz, 4H), 7.33
– 7.27 (m, 1H), 6.50 (s, 1H), 4.64 (d, J = 5.6 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.7,
138.5, 134.7, 131.9, 129.1, 128.9, 128.2, 127.9, 127.3, 44.5.
Morpholino(phenyl)methanone (8b). (Hexanes/ethyl acetate = 4:1). White solid. 1H NMR (500 MHz,
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CDCl3) δ 7.43 – 7.33 (m, 5H), 3.83 – 3.34 (m, 8H). C{1H} NMR (125 MHz, CDCl3) δ 170.7, 135.5,
130.1, 128.8, 127.3, 67.1, 48.4, 42.8.
N-(4-Methoxyphenyl)benzamide (8c). (Hexanes/ethyl acetate = 4:1). White solid. 1H NMR (500 MHz,
CDCl3) δ 7.86 (d, J = 7.3 Hz, 2H), 7.80 (s, 1H), 7.58 – 7.50 (m, 3H), 7.47 (t, J = 7.5 Hz, 2H), 6.93 –
6.87 (m, 2H), 3.81 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.0, 157.0, 135.4, 132.0, 131.4,
129.1, 127.3, 122.5, 114.6, 55.9.
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N-(tert-Butyl)benzamide (8d). (Hexanes/ethyl acetate = 4:1). White solid. 1H NMR (500 MHz, CDCl3)
δ 7.74 – 7.68 (m, 2H), 7.48 – 7.43 (m, 1H), 7.39 (t, J = 7.5 Hz, 2H), 5.96 (s, 1H), 1.47 (s, 9H). 13C{1H}
NMR (125 MHz, CDCl3) δ WS167.2, 136.3, 131.4, 128.8, 127.0, 51.9, 29.2.
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Supporting Information. NMR spectra, cartesian coordinates and energies. Detailed description of
computational methods used, full reference for Gaussian 09, energies of N-acyl-glutarimides 1–6 as
function of dihedral angle (E, kcal/mol vs. O–C–N–C [°]. Crystal data and structure refinement
summaries of 2–6, ORTEP plots of 2–6. CIF files for amides 2–6. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Author Information. Corresponding author: michal.szostak@rutgers.edu
Acknowledgements. Rutgers University and the NSF (CAREER CHE-1650766) are gratefully
acknowledged for support. The Bruker 500 MHz spectrometer was supported by the NSF-MRI grant
(CHE-1229030). We thank Jonelson Dessin (Rutgers University, ACS 2018 Project SEED) and Neyssa
Deriphonse (Rutgers University, ACS 2019 Project SEED) for assistance. We thank the Wroclaw
Center for Networking and Supercomputing (grant no. WCSS159, R.S.).
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Reactive Amide As a Transition-State Mimic For cis–trans Interconversion. J. Am. Chem. Soc. 2015,
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