Introduction

In the preceding decades, scientific breakthroughs in the field of organic chemistry have paved the way for innovative synthetic methodologies, thereby unlocking the potential to create complex molecular skeletons. One remarkable avenue in this journey has been the development of transition-metal catalyzed cross-coupling reactions, positioning them as a versatile synthetic toolbox for building chemical architectures1,2. Noteworthy examples include catalytic carbon-carbon or carbon-nitrogen bond-forming reactions, now applied for both academic research and industrial chemical synthesis (Fig. 1a)3,4. Despite the notable advances in these cross-coupling reactions, prefunctionalized aryl(alkyl) halides (or their pseudohalides) are conventionally employed to initiate the required oxidative addition, leading to the following bond-forming steps. In this context, there has been a demand for the development of new coupling protocols to utilize copious and readily obtainable aryl(alkyl) sources.

Fig. 1: Decarboxylative C–N bond couplings.
figure 1

a Transition-metal catalyzed cross-coupling reactions. b Transition-metal catalyzed decarboxylative cross-coupling reactions. c Conventional acylazide-mediated formal decarboxylative amination. d Previous approaches for the decarboxylative amination methods. e Current work: transition-metal-free stereospecific decarboxylative amidation of carboxylic acids using 1,4,2-dioxazol-5-one as an amino source.

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In response to this desire, a decarboxylative cross-coupling strategy using abundant carboxylic acid feedstocks has arisen as an appealing alternative5,6. In fact, transition-metal catalyzed decarboxylative functionalizations were developed, while they were limited mainly to aryl- or alkynylcarboxylic acid substrates under rather harsh reaction conditions (>100 oC), presumably due to the thermodynamically demanding CO2 extrusion (Fig. 1b)5. To overcome these constraints, a redox-mediated one-electron process for the decarboxylation of carboxylic acids or their derivatives, such as redox-active esters (RAEs), has been actively investigated to achieve milder cross-coupling procedures, especially to enable decarboxylative C(sp3)–N bond formation6,7, accessing one of essential biorelevant motifs prevalent in natural products, agrochemicals, and pharmaceuticals8,9,10. As note, while the conventional Curtius rearrangement or Schmidt reaction has been utilized for the formal decarboxylative amination, a significant drawback is the requirement of potentially hazardous compounds, such as azides or strong acids (Fig. 1c)11,12.

In recent years, harnessing redox-active esters, derived from carboxylic acids, has proven to be effective in facilitating C(sp3)–N bond formation under reductive decarboxylative conditions (Fig. 1d)13,14,15,16,17. While Fu and Peters pioneered a photocatalyzed intramolecular decarboxylative amidation of N-hydroxyphthalimide (NHP) esters13, MacMillan and Hu independently showcased metallaphotoredox catalysis to forge C(sp3)–N bonds in an intermolecular fashion14,15. Additionally, Lopchuck and Cornella independently reported the facile chemical reduction of RAEs using Zn(0) or Bi(I), inducing decarboxylative carboradical generation for subsequent trapping with a diazirine reagent or coupling with N-nucleophiles via radical-polar crossover, respectively16,17. Notably, Yoon unveiled an elegant decarboxylative amination procedure employing carboxylic acids directly without prior activation, wherein photoinduced ligand-to-metal charge transfer (LMCT) was utilized to engender carboradical species18,19. Despite these remarkable recent achievements, the involvement of trigonal planar carboradicals as an indispensable intermediate poses an insurmountable challenge in preserving the stereochemical information of starting materials, especially when chiral carboxylic acids are employed.

In our continuous exploration of transition-metal catalyzed nitrenoid group transfer reactions, we have demonstrated a multitude of amidation protocols utilizing 1,4,2-dioxazol-5-ones (dioxazolones), readily accessible from abundant carboxylic acids, as an efficient acylnitrenoid precursor20,21,22. Nevertheless, the use of this robust amidation reagent under metal-free conditions, bypassing the elaborated nitrenoid-involved pathways, has remained rather limited23. Drawing inspiration from the electrophilic reactivity of dioxazolones24, we hypothesized that nucleophilic addition into this amide precursor may lead to the formation of a ring-opened intermediate, to induce a subsequent rearrangement giving rise to alkyl(aryl)amides in a stereospecific manner (Fig. 1d). This conceptualization was envisaged to furnish a transition-metal-free decarboxylative amidation procedure accessing α-chiral amines when chiral carboxylic acids are used.

Herein, we present a base-mediated decarboxylative amidation of carboxylic acids to provide synthetically versatile N-alkyl(aryl)amides using easily procurable dioxazolones. This approach proved amenable to all types of carboxylic acid substrates (primary, secondary, and tertiary) under mild and ambient transition-metal-free conditions, most significantly enabling a stereoretentive transformation to access medicinally important chiral N-alkylamides. The synthetic applicability of the current reaction was underscored by high functional group tolerance as well as its scalability and ability to afford 15N-labeled compounds. Both experimental and computational mechanistic studies unveiled details on the pathway involving nucleophilic addition of carboxylate to dioxazolone, followed by sequential rearrangement and decarboxylation, eventually enabling stereoretentive amidation.

Results

Reaction optimization of transition-metal-free decarboxylative amidation

We commenced our study using cyclohexanecarboxylic acid 1 as a model substrate and assessed the reactivity of various aminating reagents (Fig. 2a). As a note, selected N-sources such as chloramine T (2a), organic azides RN3 (e.g., R = Ts; 2b and Troc; 2c), hydroxamates (e.g., 2d), and 1,4,2-dioxazol-5-ones (e.g., 2e) have been fruitfully employed in previously established amination reactions25,26,27,28,29,30. The decarboxylative amidation of 1 was not viable with such amino precursors as chloramine 2a, azides (2b, 2c) and hydroxamate 2d. In contrast, using dioxazolone 2e, the corresponding N-cyclohexylacetamide 3c was obtained, albeit in low yield (17%), in the presence of potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF) solvent.

Fig. 2: Reaction optimization of transition-metal-free decarboxylative amidation.
figure 2

a Reaction tests using a series of amination sources for decarboxylative amidation. b Reaction optimization of decarboxylative amidation using dioxazolone. Reaction conditions: cyclohexanecarboxylic acid (1, 0.1 mmol), 3-methyl-1,4,2-dioxazol-5-one (2e, 2 equiv.) and indicated base (2 equiv.) in indicated solvent (0.2 M) at room temperature for 4 h. The product yield was measured by 1H-NMR analysis of the crude reaction mixture in the presence of internal standard (1,3,5-trimethoxybenzene). DMF N,N-dimethylformamide, DMSO dimethylsulfoxide, HFIP 1,1,1,3,3,3-hexafluoroisopropanol, TEA triethylamine, DIPEA diisopropylethylamine, and DBU 1,8-diazabicyclo[5.4.0]undec-7-ene.

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Given the initial observation of the promising reactivity of the dioxazolone with carboxylic acid to yield N-alkylamide, we endeavored to optimize conditions by modulating reaction parameters (Fig. 2b, also see the Supplementary Information for details). The use of weak organic bases, including triethylamine (TEA) and diisopropylethylamine (DIPEA), proved ineffective in enhancing the reactivity (entries 2 and 3). However, significant enhancement of reactivity was observed using stronger bases (2 equiv.) such as guanidine, phosphazene, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as shown in entries 4–6, respectively. Furthermore, switching the solvent to dimethylsulfoxide (DMSO) improved the yield to 83% for the corresponding N-alkylamide 3c (entry 7). Additional screening revealed that polar aprotic solvents gave rise to moderate to high product yields (entries 6–8), while nonpolar or polar protic solvents resulted significantly reduced productivity (entries 9–11). Notably, a reaction with 25 mol% of DBU led to a moderate yield of 3c (56%, entry 12), indicative of a potential practical utility of the current amidation reaction under base-catalyzed conditions, while no reactivity observed in the absence of a base additive underscored its critical role (entry 13). Consequently, we identified the optimal amidation conditions to employ 2 equiv. of each dioxazolone and DBU in DMSO (0.2 M) at room temperature for 4 h.

Substrate scope investigations with achiral carboxylic acids

We next explored the scope of achiral carboxylic acids in the present decarboxylative amidation reaction (Fig. 3). Encouragingly, cyclic 2°-carboxylic acids readily converted into the corresponding N-cycloalkylamides under the standard conditions (3c, 4–11). Notably, cycloalkanecarboxylic acids with varying ring sizes posed no difficulty for the efficiency of the decarboxylative amidation (4–6). The sterically hindered bicyclo[2.2.1]heptan-2-yl group was also amenable, albeit in low yield (7). An N-Alkylamide incorporating a difluoromethylene moiety was efficiently obtained (8). Carboxylic acids featuring benzofused rings were smoothly converted to the desired amide products (9 and 10) and a Boc-protected amino group was well tolerated, providing the corresponding alkylamide in good yield (11). Additionally, secondary acyclic carboxylic acids proved to be viable under the current amidation conditions (12–14). It is noteworthy that the terminal alkynyl moiety, one of sensitive functional groups under basic conditions (pKa ~ 26), remained intact in this conversion giving rise to 14 in high yield.

Fig. 3: Substrate scope of decarboxylative C–N bond coupling of achiral carboxylic acids.
figure 3

Reaction conditions: carboxylic acid (0.2 mmol), 3-methyl-1,4,2-dioxazol-5-one (2e, 2 equiv.) and DBU (2 equiv.) at room temperature for 4 h. Isolated yields are reported. aRun in DMF (0.2 M). bRun for 12 h. cRun with 3 equiv. of 2e at 60 oC. SCXRD stands for single crystal X-ray diffraction.

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Subsequently, our substrate scope investigation was extended to encompass primary carboxylic acids to obtain terminal amide compounds under otherwise identical reaction conditions (15–25). It was shown that the alkyl chain length did not significantly affect the current amidation efficiency (15–17), and an α-tert-butyl group was well accommodated (18). Notably, the carbon-chloride bond, prone to cleave under radical-involved conditions via halide atom abstraction31, presented no impediment and afforded the corresponding product 19 in high yield. The successful conversion of α-cyclopropylacetic acid to N-(cyclopropylmethyl)acetamide 20 occurred without ring-opening, implying that the current decarboxylative amidation may follow a two-electron pathway rather than a radical process (vide infra)32. Intriguingly, 1,5-diacetamide (21) was also synthesized in high yield from 6-acetamidohexanoic acid in DMF solvent. Furthermore, synthetically versatile allylamide (22) was obtained from the corresponding allylic carboxylic acid33. A series of substrates containing heteroatom-functional groups, such as thiophenyl (23), benzylic ether (24), and N-phthalimide (25), were readily amenable to the reaction conditions. Furthermore, the current decarboxylative amidation approach was proven to be applicable for the synthesis of α-tertiary amides (26–31), which are usually inaccessible through the conventional reductive amination approach34,35. Notably, strained skeletons such as bicyclo[3.1.1]heptane (BCH), bicyclo[1.1.1]pentane (BCP), and cubane, extensively explored as aryl bioisosteres in the pharmaceutical community36,37, underwent smooth conversion into the desired amidated products (29–31). As a note, the intact cubane skeleton of 31 was unequivocally confirmed by a single crystal X-ray diffraction (SCXRD) analysis.

We then demonstrated that the current decarboxylative amidation could be applied for the late-stage transformation of biorelevant molecules in reaction with methyl dioxazolone 2e. A variety of non-steroidal anti-inflammatory drugs (NSAIDs), including Indomethacin (32), Loxoprofen (33), Zaltoprofen (34), and Sulindac (35), underwent successful transformations, yielding their respective N-acetamide products. Furthermore, an amidated product 36 was obtained from a carboxylic acid tethered with a steroidal backbone, lithocholic acid, and its structure was confirmed through SCXRD analysis. It is noteworthy that the unprotected alcohol, considered as a potential nucleophile, was tolerated under the current reaction conditions. We also found that α,β-unsaturated carboxylic acid readily reacted to furnish synthetically versatile enamide product 3738. Moreover, the current decarboxylative amidation was shown to be viable for establishing C(aryl)–N bonds from aryl carboxylic acids, albeit at slightly elevated temperature (38–42). Notably, the successful decarboxylative coupling of a benzoic acid derivative bearing a pinacol borate (41) holds potential for the programmable sequential C(aryl)–N couplings, by applying a Chan-Evans-Lam-type amination at the borate moiety of 4139. Decarboxylative amidation of biorelevant Adapalene (42) was also amenable.

Substrate scope investigations with chiral carboxylic acids

Optically active α-chiral amines serve as important building blocks in organic synthesis and medicinal chemistry40,41. This pharmacophore can be synthetically accessed by enantioselective reductive amination or hydrogenation of ketimine precursors40,41. In this context, we wondered whether our current decarboxylative amidation procedure could also be applied to abundant chiral carboxylic acids to obtain optically active α-chiral amines. Given that there is no precedent for stereospecific one-electron redox-mediated decarboxylative amination13,14,15,16,17,18,19, we anticipated that our envisaged stereo-controlled conversion, if applicable, would open a new avenue to access highly valuable α-chiral amines. Gratifyingly, a wide range of chiral carboxylic acids were smoothly converted into N-alkylamides in a completely stereoretentive manner (Fig. 4, 43–49). This stereospecific transformation proved effective for a broad range of carboxylic acids bearing a chiral center at the benzylic or remote alkyl position, irrespective of cyclic or acyclic molecular skeleton. Notably, chiral hemiaminal (46, 47) and aminal (48) products, typically prone to racemize easily under basic conditions due to the acidic heteroatom α-C–H bonds, could be readily obtained from the parent chiral carboxylic acids with excellent stereospecificity. Additionally, chiral diamine 49 bearing two stereogenic centers at the 1,3-position was successfully prepared from the corresponding γ-amino acid derivative (>99:1 e.r.), with the diastereomeric structure being confirmed by SCXRD.

Fig. 4: Substrate scope of decarboxylative C(sp3)–N bond coupling of chiral carboxylic acids.
figure 4

Reaction conditions: chiral carboxylic acid (0.2 mmol), dioxazolone (2 equiv.) and DBU (2 equiv.) in DMSO (0.2 M) at room temperature for 4 h. Isolated yields are reported. aRun in DMF (0.2 M) at 0 oC for 12 h. Enantiomeric ratio (e.r.) was determined by high-performance liquid chromatography (HPLC). Diastereomeric ratio (d.r.) was determined by 1H-NMR of the crude reaction mixture.

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Following this, we explored the synthetic versatility of the current stereospecific decarboxylative amidation procedure by applying it to biorelevant chiral carboxylic acids. (S)-Naproxen (50) and its brominated derivative (51) effectively underwent decarboxylative amidation using methyl dioxazolone 2e, yielding the corresponding chiral alkylamides (52 and 53, respectively). The absolute stereochemistry of 53 was unambiguously confirmed by a single-crystal X-ray diffraction analysis. Ibuprofen (54), another class of anti-inflammatory drug, was readily transformed to the desired chiral N-alkylamide with excellent stereospecificity (55, >99:1 e.r.). Chiral γ-amino acid (56) and dihydroartemisinic acid (58), each harboring multiple stereocenters, were also viable, thus producing the desired alkylamides 57 and 59, respectively, with excellent diastereoselectivity (>20:1 d.r.).

Next, we examined the scope of dioxazolones as the amino source within the framework of the current stereospecific decarboxylative amidation by employing (S)-Naproxen 50 as a model carboxylic acid (see the Supplementary Information for additional optimization studies). Notably, considering the fact that dioxazolones are easily prepared in high yields from corresponding carboxylic acids in two steps21, the present amidation can be regarded as a formal dual decarboxylative transformation of two carboxylic acid reactants. When slightly modified conditions were applied, being still mild and convenient, a range of N-alkylamides bearing various amide derivatives were readily obtained in a stereoretentive manner with high chemical yields (60–64). Notably, 3-phenylpropyl dioxazolone, previously known to transform to the 5-membered γ-lactam skeleton via metal-nitrenoid-mediated γ-C–H insertion reported by our group27, was successfully incorporated in the current decarboxylative reaction, thereby yielding the corresponding N-alkylamide with >99:1 e.r. (60). Additional types of functionalized dioxazolones featuring alkene (61) and alkyne (62) in their alkyl backbone smoothly underwent the present amidation in a stereoretentive way. As observed, the variation in enantiomeric ratio (61–63) is likely attributed to the partial involvement of decarboxylative carbanion formation in the benzylic secondary carboxylic acids42. Significantly, a dioxazolone derived from α,β-unsaturated carboxylic acid was also viable and provided the desired N-cinnamoylamide 63. Furthermore, a dioxazolone derived from oxazole containing Oxaprozin, one of the NSAIDs, was successfully subjected to the current reaction conditions, providing the corresponding product 64 (99:1 e.r.). It is noteworthy that the classical Curtius rearrangement requires additional subsequent reactions, such as the acylation of alkylamines, to prepare the above amide products tethered with a series of alkyl groups43.

Subsequently, we briefly explored the synthetic applicability of the current transition-metal-free dual-decarboxylative amidation method (Fig. 4, bottom). Firstly, a gram scale reaction was examined using (S)-Naproxen 50 with dioxazolone 2e, and similar amidation efficiency was obtained from a 10 mmol scale reaction (2 equiv. of DBU) to afford excellent product yield (92%) and stereospecificity (>99:1 e.r., entry 1). Significantly, the reaction was found to be amenable to some extent with the use of catalytic amounts of DBU and/or in nearly equimolar ratio of two reactants of 50 and 2e although chemical yields were slightly decreased, but maintaining the stereospecificity (entries 2 and 3). Next, we examined an isotopic 15N-incorporation in the amidated product given the applications of isotope-labeled compounds in metabolic mechanistic studies44,45 or in vivo imaging techniques46. A reaction of 50 with 1 equiv. of 15N-labeled methyl dioxazolone (2e-15N) readily provided the corresponding 15N-alkylamide 52-15N ( > 99:1 e.r.). It should be noted that the Curtius rearrangement requires 3 equivalents of 15N atoms (15N3–) for similar isotope labeling of carboxylic acid substrates.

Mechanistic Investigations of present transition-metal-free decarboxylative amidation using dioxazolone

Following the successful development of a transition-metal-free decarboxylative amidation under mild and ambient conditions, we further carried out mechanistic investigations of this stereoretentive transformation (Fig. 5). To elucidate the reaction pathway, density functional theory (DFT) calculations were performed (Fig. 5a, see the Supplementary Information for computational details). Computational studies indicated that nucleophilic attack of cyclohexanecarboxylate 1′ at the carbonyl carbon of dioxazolone 2e followed by carbonyl substitution via C–O bond cleavage constitutes a kinetically viable pathway {ΔG‡ (nucleophilic addition #1) = 19.1 kcal/mol and ΔG‡ (C–O bond cleavage #1) = 9.0 kcal/mol}, thus initiating the sequential processes to form a ring-opened intermediate Int1. A control experiment, employing cyclohexanecarboxylic acid 1 or its potassium salt 1′[K+], showed no reactivity with acid itself in the absence of an external base, while the use of salt gave 45% of the desired product 3c under the identical conditions, indicative of critical effect of deprotonation in the initial nucleophilic addition (Fig. 5b). Along this line, a reaction with ester 1-Me instead of carboxylic acid gave no product formation under the standard conditions (Fig. 5c).

Fig. 5: Mechanistic investigations of the transition-metal-free decarboxylative amidation.
figure 5

a DFT computed Gibbs energy and activation barrier of nucleophilic addition followed by sequential rearrangement (unit = kcal/mol). M06-2X/6-311 + G**/SMD (solvent = DMSO, ε = 46.826)//M06-2X/6-31 G**. Structure of DBUH+ and DBU is omitted for clear presentation. b Control experiment using carboxylic acid and its deprotonated form in the absence of base additive. c Reaction test using methyl cyclohexylcarboxylate (1-Me). d Crossover experiment. e Test on a symmetric intermediate Int3. cHx cyclohexyl, TBAF tetrabutylammonium fluoride, and TBS tert-butyldimethylsilyl.

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Computational studies further revealed that the subsequent intramolecular nucleophilic attack of the postulated amide anion of Int1 into the tethered carbonyl carbon (Fig. 5a) is highly facile kinetically and thermodynamically (nucleophilic addition #2: ΔG‡ = 5.4 kcal/mol, ΔG = –7.1 kcal/mol), thereby inducing the second C–O bond cleavage to afford N,N-dicarbonyl N-carbonate Int2 (C–O bond cleavage #2: ΔG‡ = 2.7 kcal/mol, ΔG = –14.2 kcal/mol). Subsequently, this intermediate Int2 extrudes CO2 to generate a symmetrical dicarbonyl-N-hydroxy species Int3 (ΔG‡ = 8.2 kcal/mol, ΔG = –1.3 kcal/mol). To substantiate the existence of the computationally estimated Int3, we designed an experiment with two different combinations of carboxylic acids and dioxazolones, namely cyclohexanecarboxylic acid (1)/3-methyl 1,4,2-dioxazol-5-one (2e) and acetic acid (65)/3-cyclohexyl 1,4,2-dioxazol-5-one (2f), to see whether a common intermediate Int3 would be formed eventually to lead to the same product 3c. Indeed, N-cyclohexylacetamide 3c was obtained exclusively from each reaction with similar efficiency. Furthermore, when tert-butyldimethylsilyl (TBS)-protected species Int3-TBS was subjected to the reaction conditions with DBU (1 equiv.) and DBU·HCl (1 equiv.), the expected product 3c was obtained by the presence of tetrabutylammonium fluoride (TBAF), likely via the in situ formation of Int3 (Fig. 5e). These combined results strongly support our working hypothesis involving Int3 as a key intermediate during the reaction course.

DFT-assisted investigations were further performed to shed light on details underpinning a plausible following rearrangement of the N-hydroxy intermediate (Fig. 6a). The hydroxy group of Int3′-A was identified as a kinetically plausible nucleophile to attack at the carbonyl carbon of the tethered acetyl moiety, thereby resulting in the formation of oxaziridine Int4-A via Int3′-A-TS (ΔG‡ = 25.4 kcal/mol). It is noteworthy that an alternative addition of the same hydroxy group of Int3 to the carbonyl carbon of the cyclohexyl instead of acetyl was found to be disfavored, presumably due to steric hindrance (see the Supplementary Information for more details). Considering that the total activation energy from Int3 to Int3′-A-TS was 28.1 kcal/mol, this step was regarded as the rate-determining step. Upon the formation of Int4-A, it was shown that the subsequent ring-opening of oxaziridine to form hydroxamate Int5-A is highly facile (ΔG‡ = 4.7 kcal/mol, ΔG = –25.9 kcal/mol). In addition, a Lossen-type rearrangement of Int5-A to lead cyclohexyl isocyanate 66 along with acetate 67 is also plausible (ΔG‡ = 25.9 kcal/mol, ΔG = –46.1 kcal/mol). As the final process, a coupling of isocyanate with carboxylate will take place to release CO2 via a Hofmann-type rearrangement to provide alkylamide product, importantly in a stereoretentive manner (Fig. 6a, right)47,48,49. In fact, in line with our proposed pathway, when an additional control experiment was conducted using hydroxamate H[Int5-A] under standard conditions, N-cyclohexylacetamide 3c was observed to form albeit at elevated temperature (Fig. 6b). It should be noted that our reaction pathway does not involve any carboradical (or carbocation) intermediates during the course of the whole processes, thus attributing to the observed excellent stereospecificity in the present decarboxylative amidation reaction (Fig. 4).

Fig. 6: Mechanistic Investigations of the C–N Coupled Product Formation.
figure 6

a Computed potential energy surface of plausible rearrangements to access N-alkylamide product (unit = kcal/mol). M06-2X/6-311 + G**/SMD (solvent = DMSO, ε = 46.826)//M06-2X/6-31 G**. b Control experiment using a postulated hydroxamate intermediate.

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In summary, we have successfully developed a stereospecific decarboxylative amidation of abundant carboxylic acids by employing 1,4,2-dioxazol-5-ones as a robust amidating reagent under mild and transition-metal-free conditions. This methodology enables a facile access to synthetically versatile N-alkylamides in a stereoretentive manner, preserving the stereochemical information of chiral carboxylic acids to provide α-chiral amines, an important pharmacophore. Through combined experimental and computational studies, we unveiled a mechanistic scaffold operative for the dioxazolone activation, and this pathway is distinctive from the previously established metal-acylnitrenoid-mediated processes. The present amidation reaction is initiated by a nucleophilic addition of carboxylate to the carbonyl of dioxazolones, followed by cascade rearrangements to offer stereospecific dual-decarboxylative pathway.

Methods

General procedure for transition-metal-free decarboxylative amination using dioxazolones

To an oven-dried 4 mL screw-capped vial equipped with oval-shaped stirring bar were added carboxylic acids (0.200 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.00 equiv., 0.400 mmol, 60.9 mg), and anhydrous dimethylsulfoxide (DMSO, 1.00 mL, 0.200 M) under atmospheric conditions. To the reaction mixture was added 3-alkyl-1,4,2-dioxazol-5-one (2.00 equiv., 0.400 mmol, 40.4 mg) and stirred for 4 h at room temperature. After reaction completion, the crude reaction mixture was diluted with dichloromethane (DCM, 5.0 mL), added 1 N HCl aqueous solution (10 mL), and extracted with DCM (5 mL × 3 times). The combined organic layer was dried over MgSO4, filtered, and concentrated under the reduced pressure. The crude mixture was subjected to silica column chromatography to provide the purified desired N-alkylamide products (eluent: Dichloromethane/Acetone, 100:0–50:50).