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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 Md. Mahbubur Rahman, Chengwei Liu, Elwira Bisz, Błazej̇ Dziuk, Roger Lalancette, Qi Wang, Hao Chen, Roman Szostak, and Michal Szostak*

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ABSTRACT: 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.

■ INTRODUCTION almost perfect twist value, τ = 89.1°. X-ray structures of five new N-acyl-glutarimides are reported. Reactivity studies in the The utility of amides in various areas of chemical science has Suzuki−Miyaura cross-coupling and transamidation reactions spurred intense research on the discovery of cross-coupling − provide insight into the reactivity of N-acyl-glutarimides in reactions by N−C(O) bond cleavage.1 3 In this regard, N-acyl- metal-catalyzed and transition-metal-free reactions. The effect glutarimides discovered by our laboratory in 2015 have of distortion, structures, and the rotational barrier around the become the reagents of choice for the development and N−C(O) axis is discussed. Collectively, the ability to achieve optimization of new cross-coupling reactions by N−C(O)

Downloaded via 76.117.163.167 on April 10, 2020 at 01:23:22 (UTC). fi 4−6 full distortion of the amide bond signi cantly expands the bond activation (Figure 1). A common element for all range of reagents available for N−C(O) cross-coupling successful amide precursors developed to date for cross- reactions. coupling reactions is ground-state destabilization of the amide bond, which permits for highly selective oxidative addition of RESULTS AND DISCUSSION

See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. ■ the N−C(O) bond to form a stable acyl−metal complex,7 despite the traditional high amidic resonance of planar amide The planarity of the amide bond is a fundamental property of amides described in all organic chemistry textbooks.1,2 bonds (n → π* conjugation, 15−20 kcal/mol in planar −N C O amides).8 17 Whereas in classical amides, coplanarity of the six atoms comprising the amide bond results in low reactivity of amide Given that NH-glutarimides are cheap, commercially 8,9 available, or readily synthesized from the corresponding linkages, geometrical distortion of the amide bond from 18 planarity brings about significantly enhanced reactive proper- glutaric acids, and thus far represent the only class of 10−17 amide precursors that have enabled close to full distortion of ties of amides. Conventionally, distortion of the amide bond from planarity has been achieved by placing the nitrogen the amide bond that translates to the development of a wide 10,17b − atom in a rigid bicyclic ring system. In recent years, 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 a Received: January 29, 2020 glutarimide ring on the structures, electronic properties, and Published: March 11, 2020 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

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.joc.0c00227 A J. Org. Chem. XXXX, XXX, XXX−XXX The Journal of Organic Chemistry pubs.acs.org/joc Article

Figure 2. Structures of N-acyl-glutarimides used in this study.

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 gluta- rimide (2), 3,3-tetramethylene glutarimide (3), 3,3-pentam- ethylene 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 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 fi − − and structure re nement summaries for 2 6 are included in Figure 1. (a) Amide N C bond activation. (b) N-Acyl-glutarimides: − the most reactive and versatile amides in N−C bond cross-coupling. the Supporting Information,TablesS1S2. The X-ray structure of the parent amide 1 has been previously reported.7a − The Winkler Dunitz distortion parameters (τ, χN), the Σ geometric distortion of acyclic amides has emerged as an additive distortion parameter (τ + χN), and selected bond effective way to commonly employ these twisted amides in lengths of amides 1−6 are summarized in Table 1. For cross-coupling reactions.19 To date, only N-acyl-glutarimide comparison, Table 1 also includes fully perpendicular model amides have come close to achieving the full distortion of the bridged lactam, 2-quinuclidonium tetrafluoroborate, and planar amide bond,7a rendering them the reagents of choice for cross- formamide. coupling reactions. To expand the range of N-acyl-glutarimide The structures of amides 1−6 are presented in Figure 3 amides available for cross-coupling reactions to the broad together with their Newman projections along the N−C(O) synthetic community, we conducted a study of the effect of an bonds. All structures have been deposited with the Cambridge N-glutarimide ring on the structure, and electronic and reactive Crystallographic Data Center as supplementary publication no. properties of N-acyl-glutarimides. N-Acyl-glutarimides have 1969082 (2), 1969086 (3), 1969087 (4), 1969085 (5), been selected for this study because of a much higher reactivity 1969088 (6). The expanded ORTEP structures of amides 1−6 in N−C(O) cross-coupling reactions than N-acyl-succini- are presented in the Supporting Information. − mides,4 6 which is related to the higher twist angle of N- Most interestingly, the X-ray structures of N-acyl-gluta- acyl-glutarimides.7 It is also worth noting that di-substituted rimides 1−6 demonstrate that these compounds are among the glutarimides are readily available from the corresponding most twisted amides structurally characterized to date, with glutaric acids by one-pot amidation/cyclization,18 which twist angles (τ) ranging from 77.7 to 89.1°. Remarkably, the should facilitate fine-tuning of N-acyl-glutarimides for N− 3,3-tetramethylene derivative (3) is characterized by the most C(O) cross-couplings, including by decarbonylative pathways. twisted acyclic amide bond in this series crystallized to date (τ More broadly, N-acyl-glutarimides can be regarded as “not = 89.1°; cf. parent N-benzoyl-glutarimide, τ = 87.5°).7a In additionally stabilized” amides. N-Acylation and related types contrast, the nitrogen atom remains practically planar, with ff ° of Nlp delocalization exert a substantial e ect on the electronic (χN) ranging from 5.6 to 8.7 . Thus, these compounds are properties of amides. Studies are ongoing to provide a categorized as classic twisted amides according to the Yamada comprehensive survey of changes in amidic resonance in classification.15 commonly used amides and derivatives, wherein it appears that The N−C(O) bond length varies from 1.455 Å (3) to 1.475 triacyl derivatives, such as N-acyl-glutarimides, represent an Å(1 and 2), whereas the CO bond length is between 1.186 extreme case of nonstabilized, perfectly twisted, yet stable Å(4) and 1.218 Å (2). There appears to be no clear amide derivatives.7a,b correlation involving Winkler−Dunitz parameters and bond Crystallographic Studies. The structures of N-acyl- lengths, likely because of their placement at the extreme glutarimides (1−6) selected for the study are shown in Figure maximum of the amide bond distortion. It is useful to compare 2. The parent N-benzoyl-glutarimide (1) has been previously (i) the N−C(O) bond lengths in neutral 1−6 (average of reported by us, and represents the only compound in this class 1.467 Å) with the N-protonated 2-quinuclidonium tetrafluor- − developed to date.4 7 All N-acyl-glutarimides were synthesized oborate (1.524 Å) and formamide (1.349 Å), and (ii) the C in 78−96% yields on a gram scale from the corresponding acyl O bond lengths in 1−6 (average of 1.199 Å) with the N- chlorides (see the Supporting Information) and purified by protonated 2-quinuclidonium tetrafluoroborate (1.192 Å) and

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a Table 1. Selected Crystallographic Structural Parameters of N-Acyl-glutarimides 1−6 and Representative Amides −  entry amide N C(O) [Å] C O [Å] τ [deg] χN [deg] τ + χN [deg] 1a 1 1.476 1.201 87.48 5.60 93.08 2b 2 1.475 1.218 87.69 7.00 94.69 3b 3 1.455 1.202 89.08 7.02 96.10 4b 4 1.459 1.186 77.72 8.69 86.41 5b 5 1.467 1.192 83.35 6.91 90.26 6b 6 1.473 1.196 85.95 5.77 93.07 7c 2-quinuclidonium tetrafluoroborate 1.526 1.192 89.12 59.475 148.60 8d formamide 1.349 1.193 0.0 0.0 0.0 aref 7a. bThis study. X-ray structures. cref 10a. dCalculated values. Reference 11a.

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 the Supporting Information 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). planar formamide (1.193 Å). The order of distortion based on (45%). Thus, the Suzuki−Miyaura cross-coupling with amides the X-ray data in the series 1−6 is as follows: 3 > 2 > 1 > 6 > 5 1−6 established (i) excellent reactivity of 1−6 under the > 4, with the maximum additive distortion parameter11d Σ(τ + model reaction conditions (conditions A−D), and (ii) ° − fi χN) of 96.1 reached by amide 3 (vide infra). Interestingly, the demonstrated that amides 1 6 show signi cant variations C3-geminal substitution does not have a major effect on the N- under aqueous conditions (conditions E), which is likely due acyl amide bond distortion (eclipsed CO/C3−Me con- to lower solubility of the less reactive amides in the solvent formation, transannular distance between C3−Me hydrogen system. and CO of 3.554 Å). To gain further insight into the reactivity of fully twisted Reactivity Studies. Having established the extreme amides 1−6 in the Suzuki−Miyaura cross-coupling, we distortion of amides in the series 1−6, we were keen to conducted kinetic studies (Table 3 and Figure 4). For this examine their reactivity in the model Suzuki−Miyaura cross- study we employed nonaqueous conditions at 1.0 mol % coupling reaction (Table 2). We selected conditions catalyzed catalyst loading. Interestingly, we found that while amides 1−5 by [Pd(IPr)(cin)Cl] (cin = cinnamyl, IPr = 1,3-bis(2,6- showed similar reaction kinetics with full conversion observed diisopropylphenyl)imidazo-2-ylidene)3a,22 because of the after approximately 20 min, the naphthalene derivative 6 was beneficial properties of the well-defined Pd(II)−NHC significantly slower to react, reaching full conversion after precatalysts and well-established catalytic cycle. approximately 60 min. Thus, a difference in reactivity resulting As summarized in Table 2, the model Suzuki−Miyaura from variations in solubility is an important parameter to keep cross-coupling using 4-tolylboronic acid proceeded in excellent in mind when optimizing cross-coupling reactions with N-acyl- yields with all compounds 1−6 at 3 mol % (conditions A) and glutarimides. In particular, the slow release of amide 6 could be 1 mol % (conditions B) catalyst loading (quantitative beneficial for cross-coupling reactions, especially in cases when conversions). Furthermore, decreasing the catalyst loading to a small concentration of the reagent is needed for optimal 0.10 mol % (conditions C) resulted in uniformly high TON results. (TON = turnover number) of 820−860 with all amides 1−6, To further probe the reactivity of amides 1−6 in the model whereas a further decrease in catalyst loading to 0.05 mol % Suzuki−Miyaura cross-coupling, we conducted a comparative (conditions D) gave 31−38% conversions with all compounds study using representative electron-rich, electron-withdrawing, 1−6. Moreover, we tested the aqueous conditions at 1.0 mol % and sterically demanding boronic acids as the cross-coupling catalyst loading (conditions E). Interestingly, under these partners (Table 4). Pleasingly, we found that all amides 1−6 conditions we found that N-acyl-glutarimides 3 (85%) and 4 showed excellent reactivity using electron-rich boronic acids (72%) are more reactive than amides 1 (56%) and 2 (61%) (4-tolylboronic acid and 4-methoxyphenylboronic acid, and significantly more reactive than amides containing quantitative conversions), whereas the reactions using aromatic rings in the glutarimide part, 5 (27%) and 6 challenging electron-poor 4-trifluromethylphenylboronic acid

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a Table 2. Effect of the Glutarimide Ring on Suzuki−Miyaura Cross-Coupling by N−C Bond Cleavage

a − ° Conditions: 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].

(80−89%) and sterically demanding 2-tolylboronic acid (97%- Computational Studies. We also conducted computa- quantitative) showed acceptable and excellent reactivity, tional studies to gain additional insight into the structures and respectively. Importantly, the cleavage of the alternative N− ground-state-destabilization of twisted N-acyl-glutarimides 1− C(O) bond of the glutarimide ring was not observed under any 6 (Tables 6−7 and Figure 5). The B3LYP/6-311++G(d,p) of the conditions, attesting to the high capacity of amides 1−6 level was selected to conduct geometry optimization because of to serve as N−C(O) cleavage precursors in transition-metal good reproducibility of literature data and method practicality. catalysis. Most importantly, optimization of the geometries of amides The influence of the glutarimide ring on transition-metal- 1−6 clarifies the data obtained from the X-ray crystallography. free reactions was also examined (Table 5).23 We selected It is well-established that crystal packing and nonbonding transamidation reactions under additive-free conditions as our interactions might impact structural parameters of the amide model system because these reactions represent arguably the bond, whereas a combined approach based on computational most convenient method to perform transamidations24,25 to evaluation of crystallographically determined amides in a series construct new amide bonds under mild conditions. As shown of compounds provides a reliable pathway to elucidate ground- in Table 5, all amides 1−6 showed excellent reactivity using state destabilization of amides. Thus, the Winkler−Dunitz nucleophilic benzylamine (conditions A) and more challenging distortion parameters (τ, χN), the additive distortion parameter Σ − morpholine (conditions B), resulting in quantitative con- (τ + χN), and selected bond lengths of amides 1 6 optimized versions at room temperature in the absence of any additives. at the B3LYP/6-311++G(d,p) level are listed in Table 6.We Moreover, these reagents enable for the first time to use non- employed X-ray structures of amides 1−6 as the starting nucleophilic p-anisidine (conditions C−D) and sterically geometry and performed full optimization. The computation- hindered tert-butylamine (conditions E−F) as nucleophiles. ally determined structures of amides 1−6 are presented in Whereas in these more challenging cases, a higher temperature Figure 5. Figure 5 also shows Newman projections along the is required for transamidation, it is very interesting to note that N−C(O) bonds in the ground-state (blue box) and Newman the new reagents 2−6 show a significantly higher reactivity projections along the N−C(O) bonds at the maximum (red than the parent N-benzoyl-glutarimide 1 (71−83 vs 27%, box) (Table 7, vide infra). conditions D, and 91−97 vs 49%, conditions F). Thus, the new Interestingly, we found that the order of distortion for twisted amides 2−6 might find applications not only in the amides 1−6 determined by computations is as follows: 4 > 2 > transition-metal catalysis but also in the emerging manifold of 3 > 1 = 5 > 6. Furthermore, computations demonstrate that transition-metal-free acyl activation reactions23 of the amide the main difference in distortion of amides 1−6 arises from ° bond. nitrogen pyramidalization (χN) ranging from 6.6 to 9.1 ,

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a Table 3. Reactivity of N-Acyl-glutarimides 1−6 in Suzuki−Miyaura Cross-Coupling

a − ° − 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. Percentage yield is shown.

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 are shown in Table 7, whereas a graphical representation of 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, whereas the energy reaches a 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), whereas 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 Figure 4. Kinetic profile of N-acyl-glutarimides 1−6 in Suzuki− main factor responsible for the high reactivity of acyclic twisted Miyaura cross-coupling. Conditions: amide (1.0 equiv), Ar−B(OH) amides in chemoselective reactions involving activation of the 2 − (2.0 equiv), [Pd] (1.0 mol %), K2CO3 (3.0 equiv), THF (0.25 M), 60 N C(O) bond in transition-metal catalysis and nucleophilic °C, 5-60 min. acyl addition reactions. ■ CONCLUSIONS whereas all amides 1−6 are practically perpendicular in the gas In summary, we have reported a full study on the effect of a phase: (τ) ranging from 89.8 to 90.0°. Whereas the observed glutarimide ring on the structures, reactivity, and electronic differences are relatively small, the observed trend is consistent properties of fully perpendicular N-acyl-glutarimide amides. ff with an increased nitrogen pyramidalization (χN)eected by We have established the generality of the amide bond twist in electron-donating groups adjacent to the amide bond.19 the class of reagents that have been shown as the most reactive

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a Table 4. Reactivity of N-Acyl-glutarimides 1−6 in Suzuki−Miyaura Cross-Coupling with Various Boronic Acids

a − ° 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, 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. in the powerful manifold of amide bond N−C(O) cross- All other general methods have been published.4a,b 1H NMR and 13C coupling. This study reports the most twisted N-acyl- NMR data are given for all compounds in the supporting experimental glutarimide discovered to date with an almost perfect twist for characterization purposes. 1H NMR, 13C NMR, and HRMS data value determined crystallographically, τ = 89.1°. Examination are reported for all new compounds. N of the reactivity of N-acyl-glutarimide amides in the model General Procedure for the Synthesis of -Acyl-glutari- mides. 4a,b Suzuki−Miyaura cross-coupling and transamidation reactions A previously published procedure was followed. An oven- dried round-bottomed flask equipped with a stir bar was charged with provided insight into the reactivity and established new more an amine substrate (typically, 1.0−10.0 mmol, 1.0 equiv), 4- reactive N-acyl-glutarimides for both classes of reactions. (dimethylamino)pyridine (typically, 0.10 equiv) triethylamine (typ- Computational studies provided insight into the distortion and ically, 2.0 equiv), and dichloromethane (typically, 0.25 M). Benzoyl rotational barriers of N-acyl-glutarimides. Remarkably, these chloride (typically, 1.5 equiv) was added dropwise to the reaction N-acyl-glutarimides are uniformly characterized by extremely mixture with vigorous stirring at 0 °C, and the reaction mixture was Δ − high barriers to rotation ( E = approx. 12 13 kcal/mol) in stirred for 15 h at room temperature. After the indicated time, the rotationally inverted scaffolds (energy minimum at 90°). The reaction mixture was washed with quenched HCl (aq, 1.0 N, 1 × 20 capacity to fully twist the amide bond in a wide range of N- mL), extracted with dichloromethane (2 × 20 mL), the organic layers acyl-glutarimides significantly expands the access to novel were combined dried and concentrated. Purification by chromatog- reagents for the development of new N−C(O) bond activation raphy on silica gel (hexanes/ethyl acetate = 1:1) or recrystallization reactions. (toluene) afforded the title products. Amide 1 has been previously reported in the literature.4a ■ EXPERIMENTAL SECTION Spectroscopic properties matched literature data. Amides 2, 3, 4, 5, General Methods. All compounds reported in the paper have and 6 are new compounds. All amides were fully characterized by X- been previously described in literature or prepared by the method ray crystallographic analysis. Note: in our experience, N-acyl- reported previously unless stated otherwise. All experiments involving glutarimides are bench-stable, easy to purify solids. We have not palladium were performed using standard Schlenk techniques under noticed any decomposition when storing at the bench-top over the nitrogen or argon unless stated otherwise. All solvents were purchased course of >6 months. at the highest commercial grade and used as received or after 1-Benzoylpiperidine-2,6-dione (1). Yield 84% (1.10 g). (Hexanes/ 1 purification by distillation from sodium/benzophenone under nitro- ethyl acetate = 1:1). White solid. H NMR (500 MHz, CDCl3): δ gen. All solvents were deoxygenated prior to use. All other chemicals 7.90−7.81 (m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), were purchased at the highest commercial grade and used as received. 2.74 (t, J = 6.6 Hz, 4H), 2.10 (quint, J = 6.6 Hz, 2H). 13C{1H} NMR

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Table 5. Reactivity of N-Acyl-glutarimides 1−6 in Transamidation Reactions with Various Amines5

a ° Conditions: 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.

a Table 6. Energies and Selected Structural Parameters of N-Acyl-glutarimides 1−6 (B3LYP/6-311++G(d,p)) − −  entry amide ET [au] N C(O) [Å] C O [Å] τ [deg] χN [deg] τ + χN [deg] 1 1 744.56085 1.493 1.198 90.00 7.25 97.25 2 2 823.21112 1.491 1.198 90.00 8.99 98.99 3 3 900.64228 1.491 1.198 89.82 8.33 98.15 4 4 939.97320 1.491 1.198 89.83 9.08 98.91 5 5 975.66608 1.493 1.198 90.00 7.22 97.22 6 6 1011.38316 1.492 1.198 90.00 6.56 96.56 aFor structures, see Figure 5.

Table 7. Energies of N-Acyl-glutarimides 1−6 as a Function 1-Benzoyl-4,4-dimethylpiperidine-2,6-dione (2). Yield 86% (1.27 1 of the Dihedral Angle (ΔE, kcal/mol vs O−C−N−C[°] g). (Hexanes/ethyl acetate = 1:1). White solid. mp 155−156 °C. H a − (B3LYP/6-311++G(d,p))) 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} Δ E [kcal/mol] NMR (125 MHz, CDCl3): δ 171.8, 171.2, 135.2, 132.4, 130.5, 129.4, + entry amide −20° −10° 0° 10° 20° 90° 46.3, 30.3, 28.3. HRMS (ESI) m/z:[M+H] calcd for C14H16NO3, 246.1125; found, 246.1124. 1 1 6.794 11.928 10.741 8.491 6.370 0.018 8-Benzoyl-8-azaspiro[4.5]decane-7,9-dione (3). Yield 94% (1.52 2 2 6.709 11.840 10.788 9.043 6.650 0.022 g). (Hexanes/ethyl acetate = 1:1). White solid. mp 139−140 °C. 1H 3 3 6.476 11.816 10.777 8.986 6.597 0.025 − NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 8.3, 1.1 Hz, 2H), 7.66 4 4 4.743 11.772 10.700 8.882 6.516 0.017 7.61 (m, 1H), 7.49 (t, J = 7.8 Hz, 2H), 2.71 (s, 4H), 1.82−1.76 (m, 5 5 6.646 11.981 10.677 8.413 6.292 0.018 − 13 4H), 1.70 1.67 (m, 4H). C{1H} NMR (125 MHz, CDCl3): δ 6 6 7.499 13.112 11.879 10.050 7.499 0.014 172.0, 171.2, 135.2, 132.3, 130.5, 129.4, 44.9, 40.6, 38.3, 24.7. HRMS a + 1: ΔE = 0 kcal/mol at 86.38° O−C−N−C; 2, 85.51° O−C−N−C; (ESI) m/z:[M+H] calcd for C16H18NO3, 272.1281; found, 3, 85.64° O−C−N−C; 4, 85.65° O−C−N−C; 5, 86.38° O−C−N− 272.1280. C; 6, 86.72° O−C−N−C. See the Supporting Information for details. 3-Benzoyl-3-azaspiro[5.5]undecane-2,4-dione (4). Yield 96% (1.10 g). (Hexanes/ethyl acetate = 1:1). White solid. mp 175−176 ° 1 − (125 MHz, CDCl3): δ 172.3, 171.1, 135.3, 132.0, 130.4, 129.4, 32.6, C. H NMR (500 MHz, CDCl3): δ 7.90 7.83 (m, 2H), 7.64 (t, J = 17.7. 7.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 2.68 (s, 4H), 1.57 (s, 8H), 1.49

G https://dx.doi.org/10.1021/acs.joc.0c00227 J. Org. Chem. XXXX, XXX, XXX−XXX The Journal of Organic Chemistry pubs.acs.org/joc Article

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).

the reaction mixture was cooled down to room temperature, diluted fi with CH2Cl2 (10 mL), ltered, and concentrated. A sample was 1 − analyzed by H NMR (CDCl3, 500 MHz) and/or GC MS to obtain conversion, selectivity, and yield using an internal standard and comparison with authentic samples. The 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 Loadings. 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] (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 Figure 6. Rotational barriers of amides 1−6 (kcal/mol). Note that the (10 mL), filtered, and concentrated. A sample was analyzed by 1H − barriers represent energies required to reach planarity by fully twisted NMR (CDCl3, 500 MHz) and/or GC MS to obtain conversion, N−C(O) bonds. selectivity, and yield using an internal standard and comparison with authentic samples. The analytical sample was purified by chromatog- raphy on silica gel (hexanes/ethyl acetate = 1:1) for characterization 13 (s, 2H). C{1H} NMR (125 MHz, CDCl3): δ 171.8, 171.2, 135.2, purposes. 132.4, 130.6, 129.4, 44.2, 36.7, 33.2, 25.9, 21.8. HRMS (ESI) m/z:[M General Procedure for the Suzuki−Miyaura Cross-Coupling + ff +H] calcd for C17H20NO3, 286.1438; found, 286.1436. at Di erent Reaction Times. An oven-dried vial equipped with a 1-Benzoyl-4-phenylpiperidine-2,6-dione (5). Yield 82% (1.46 g). stir bar was charged with an amide substrate (neat, 1.0 equiv), (Hexanes/ethyl acetate = 1:1). White solid. mp 117−118 °C. 1H potassium carbonate (3.0 equiv), boronic acid (2.0 equiv), [Pd(IPr)- NMR (500 MHz, CDCl3): δ 7.81 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.4 (cin)Cl] (1 mol %), placed under a positive pressure of argon, and Hz, 1H), 7.49−7.40 (m, 4H), 7.35 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 7.4 subjected to three evacuation/backfilling cycles under high vacuum. Hz, 2H), 3.65−3.57 (m, 1H), 3.11−2.97 (m, 4H). 13C{1H} NMR THF (0.25 M) was added with vigorous stirring at room temperature; ° (125 MHz, CDCl3): δ 171.4, 170.8, 140.2, 135.3, 132.0, 130.6, 129.6, the reaction mixture was placed in a preheated oil bath at 60 C and 129.4, 128.2, 126.8, 39.7, 35.2. HRMS (ESI) m/z:[M+H]+ calcd for stirred for the indicated time. After the indicated time, the reaction C18H16NO3, 294.1125; found, 294.1123. mixture was cooled down to room temperature, diluted with CH2Cl2 2-Benzoyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (6). Yield (10 mL), filtered, and concentrated. A sample was analyzed by 1H − − 78% (2.38 g). (Hexanes/ethyl acetate = 1:1). Red solid. mp 228 NMR (CDCl3, 500 MHz) and/or GC MS to obtain conversion, ° 1 229 C. H NMR (500 MHz, CDCl3): δ 8.62 (d, J = 7.2 Hz, 2H), selectivity, and yield using an internal standard and comparison with 8.32 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 7.5 Hz, 2H), 7.81 (t, J = 7.7 Hz, authentic samples. The analytical sample was purified by chromatog- 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H). 13C{1H} NMR raphy on silica gel (hexanes/ethyl acetate = 1:1) for characterization (125 MHz, CDCl3): δ 170.8, 163.9, 135.4, 135.3, 132.4, 132.2, 132.0, purposes. 130.8, 129.5, 129.2, 127.5, 122.4. HRMS (ESI) m/z:[M+H]+ calcd General Procedure for the Suzuki−Miyaura Cross-Coupling ff for C19H12NO3, 302.0812; found, 302.0810. with Di erent Boronic Acids. An oven-dried vial equipped with a General Procedure for the Suzuki−Miyaura Cross-Coupling. stir bar was charged with an amide substrate (neat, 1.0 equiv), An oven-dried vial equipped with a stir bar was charged with an amide potassium carbonate (3.0 equiv), boronic acid (2.0 equiv), [Pd(IPr)- substrate (neat, 1.0 equiv), potassium carbonate (typically, 3.0 equiv), (cin)Cl] (1 mol %), placed under a positive pressure of argon, and boronic acid (typically, 2.0 equiv), Pd−NHC precatalyst (typically, 3 subjected to three evacuation/backfilling cycles under high vacuum. mol %), placed under a positive pressure of argon, and subjected to THF (0.25 M) was added with vigorous stirring at room temperature; three evacuation/backfilling cycles under high vacuum. THF the reaction mixture was placed in a preheated oil bath at 60 °C and (typically, 0.25 M) was added with vigorous stirring at room stirred for the indicated time. After the indicated time, the reaction temperature; the reaction mixture was placed in a preheated oil bath mixture was cooled down to room temperature, diluted with CH2Cl2 at 60 °C and stirred for the indicated time. After the indicated time, (10 mL), filtered, and concentrated. A sample was analyzed by 1H

H https://dx.doi.org/10.1021/acs.joc.0c00227 J. Org. Chem. XXXX, XXX, XXX−XXX The Journal of Organic Chemistry pubs.acs.org/joc Article − − NMR (CDCl3, 500 MHz) and/or GC MS to obtain conversion, 7.48 7.43 (m, 1H), 7.39 (t, J = 7.5 Hz, 2H), 5.96 (s, 1H), 1.47 (s, 13 selectivity, and yield using an internal standard and comparison with 9H). C{1H} NMR (125 MHz, CDCl3): δ WS167.2, 136.3, 131.4, authentic samples. The analytical sample was purified by chromatog- 128.8, 127.0, 51.9, 29.2. raphy on silica gel (hexanes/ethyl acetate = 1:1) for characterization purposes. ■ ASSOCIATED CONTENT General Procedure for Transamidation Reactions. An oven- ı dried vial equipped with a stir bar was charged with an amide *s Supporting Information substrate (neat, 1.0 equiv), CH3CN (typically, 0.50 M), and amine The Supporting Information is available free of charge at (typically, 2.0 equiv) with vigorous stirring at room temperature. The https://pubs.acs.org/doi/10.1021/acs.joc.0c00227. reaction mixture was stirred at the indicated temperature for 15 h. After the indicated time, the reaction mixture was diluted with EtOAc NMR spectra, cartesian coordinates and energies; (10 mL), washed with aqueous HCl (aq, 0.50 N, 5 mL), the aqueous detailed description of computational methods used, layer was extracted with EtOAc (2 × 5 mL), the organic layers were full reference for Gaussian 09, energies of N-acyl- combined, dried, filtered, and concentrated. A sample was analyzed by glutarimides 1−6 as a function of dihedral angle ΔE, 1 − − − − ° H NMR (CDCl3, 500 MHz) and/or GC MS to obtain conversion, kcal/mol vs O C N C[]; and crystal data and selectivity, and yield using an internal standard and comparison with structure refinement summaries of 2−6, ORTEP plots of authentic samples. The analytical sample was purified by chromatog- 2−6 (PDF) raphy on silica gel (hexanes/ethyl acetate = 1:1) for characterization fi − purposes. CIF les for amides 2 6 (CIF) Characterization Data of Cross-Coupling and Transamida- tion Products. All products reported in this paper have been 4a 4a 4a 4a 26 26 26 26 ■ AUTHOR INFORMATION previously reported: 7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d. Spectroscopic data matched those reported in the literature. Corresponding Author Compounds 7a, 7b, 7c, 7d, 8a, 8c, 8d have been quantified by 1H Michal Szostak − Department of Chemistry, Rutgers University, NMR spectroscopy (500 MHz) using nitromethane as the internal Newark, New Jersey 07102, United States; orcid.org/0000- standard. Analytical samples were isolated for characterization 0002-9650-9690; Email: [email protected] purposes. Phenyl(p-tolyl)methanone (7a). (Hexanes/ethyl acetate = 10:1). Authors 1 − White solid. H NMR (500 MHz, CDCl3): δ 7.83 7.75 (m, 2H), Md. Mahbubur Rahman − Department of Chemistry, Rutgers 7.73 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, University, Newark, New Jersey 07102, United States 2H), 7.28 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR (125 Chengwei Liu − Department of Chemistry, Rutgers University, MHz, CDCl3): δ 196.8, 143.5, 138.3, 135.2, 132.5, 130.6, 130.2, 129.3, 128.5, 21.9. Newark, New Jersey 07102, United States; orcid.org/0000- (4-Methoxyphenyl)(phenyl)methanone (7b). (Hexanes/ethyl ac- 0003-1297-7188 1 − − etate = 1:10). White solid. H NMR (500 MHz, CDCl3): δ 7.85 7.79 Elwira Bisz Department of Chemistry, Opole University, Opole (m, 2H), 7.78−7.71 (m, 2H), 7.58−7.52 (m, 1H), 7.46 (t, J = 7.6 Hz, 45-052, Poland; orcid.org/0000-0002-7070-2468 2H), 6.98−6.93 (m, 2H), 3.87 (s, 3H). 13C{1H} NMR (125 MHz, Błazej̇ Dziuk − Department of Chemistry, Opole University, CDCl3): δ 195.8, 163.5, 138.6, 132.8, 132.2, 130.4, 130.0, 128.5, Opole 45-052, Poland; Faculty of Chemistry, Wrocław 113.8, 55.8. University of Science and Technology, 50-373 Wrocław, Poland fl 7c Phenyl(4-(tri uoromethyl)phenyl)methanone ( ). (Hexanes/ Roger Lalancette − Department of Chemistry, Rutgers 1 δ ethyl acetate = 10:1). White solid. H NMR (500 MHz, CDCl3): University, Newark, New Jersey 07102, United States; 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, 2H), 7.65−7.60 (m, 1H), 7.51 (t, J = 7.7 Hz, 2H). 13C{1H} orcid.org/0000-0002-3470-532X Qi Wang − Department of Chemistry & Environmental Science, 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 = New Jersey Institute of Technology, Newark, New Jersey 07102, 19 − 273.13 Hz). F NMR (471 MHz, CDCl3): δ 63.01. United States Phenyl(o-tolyl)methanone (7d). (Hexanes/ethyl acetate = 10:1). Hao Chen − Department of Chemistry & Environmental 1 − Colorless oil. H NMR (500 MHz, CDCl3): δ 7.85 7.76 (m, 2H), Science, New Jersey Institute of Technology, Newark, New Jersey 7.61−7.56 (m, 1H), 7.46 (t, J = 7.5, 2H), 7.40 (td, J = 7.5, 1.3 Hz, 07102, United States; orcid.org/0000-0001-8090-8593 1H), 7.31 (dd, J = 11.8, 7.1 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 2.34 (s, Roman Szostak − Department of Chemistry, Wroclaw 13 δ 3H). C{1H} NMR (125 MHz, CDCl3): 198.9, 138.9, 138.1, University, Wroclaw 50-383, Poland 137.0, 133.4, 131.3, 130.5, 130.4, 128.8, 128.8, 125.5, 20.3. N-Benzylbenzamide (8a). (Hexanes/ethyl acetate = 4:1). White Complete contact information is available at: 1 solid. H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 7.7 Hz, 2H), 7.50 https://pubs.acs.org/10.1021/acs.joc.0c00227 (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} Notes δ NMR (125 MHz, CDCl3): 167.7, 138.5, 134.7, 131.9, 129.1, 128.9, The authors declare no competing financial interest. 128.2, 127.9, 127.3, 44.5. Morpholino(phenyl)methanone (8b). (Hexanes/ethyl acetate = 1 − ■ ACKNOWLEDGMENTS 4:1). White solid. H NMR (500 MHz, CDCl3): δ 7.43 7.33 (m, − 13 5H), 3.83 3.34 (m, 8H). C{1H} NMR (125 MHz, CDCl3): δ Rutgers University and the NSF (CAREER CHE-1650766) 170.7, 135.5, 130.1, 128.8, 127.3, 67.1, 48.4, 42.8. are gratefully acknowledged for support. The Bruker 500 MHz 8c N-(4-Methoxyphenyl)benzamide ( ). (Hexanes/ethyl acetate = spectrometer was supported by the NSF-MRI grant (CHE- 1 δ 4:1). White solid. H NMR (500 MHz, CDCl3): 7.86 (d, J = 7.3 Hz, 1229030). We thank Jonelson Dessin (Rutgers University, 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, ACS 2018 Project SEED) and Neyssa Deriphonse (Rutgers University, ACS 2019 Project SEED) for assistance. We thank CDCl3): δ 166.0, 157.0, 135.4, 132.0, 131.4, 129.1, 127.3, 122.5, 114.6, 55.9. the Wroclaw Center for Networking and Supercomputing N-(tert-Butyl)benzamide (8d). (Hexanes/ethyl acetate = 4:1). (grant no. WCSS159, R.S.). Q.W. and H.C. are thankful to the 1 − White solid. H NMR (500 MHz, CDCl3): δ 7.74 7.68 (m, 2H), support of NSF (CHE-1915878).

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