Introduction

For α-chiral carboxylic acids, decarboxylative C–N bond formation involves two interrelated challenges: the carboxyl group must depart as CO₂, while the spatial configuration of the chiral carbon adjacent to the carboxyl group should be retained as much as possible.

Many modern decarboxylative coupling reactions employ single-electron processes to generate carbon-centered radicals, followed by subsequent bond formation. For chiral carboxylic acids, however, such pathways present a stereochemical problem: many common carbon-centered radicals are nearly planar or have low barriers to configurational inversion, so the stereochemical information carried by the starting carboxylic acid can readily erode at the radical stage. In 2024, Kweon, Park, Kim, and Chang reported a stereoretentive decarboxylative amidation involving dioxazolones. The reaction begins with nucleophilic addition of a carboxylate to a dioxazolone and proceeds through consecutive two-electron rearrangements and two decarboxylation events to furnish N-alkyl amides, displaying high stereospecificity across a range of chiral carboxylic acids.[1]

The key mechanistic question raised by this reaction is: why can the original stereochemical information be retained after the carboxyl group has been removed?

1. Why Single-Electron Decarboxylation Readily Leads to Loss of the Original Stereochemical Information

1.1 α-Chiral carboxylic acids carry spatial information at a tetrahedral carbon center

A representative α-chiral carboxylic acid can be written as:

R¹R²C*(H)–CO₂H

C* represents the chiral carbon atom. Four different substituents around this carbon define a specific three-dimensional arrangement, which constitutes the stereochemical information of the starting material.

In a common single-electron decarboxylation pathway, a carboxylic acid or a preactivated carboxylic acid derivative can undergo electron transfer and CO₂ extrusion to generate the corresponding carbon-centered radical:

R¹R²C*(H)–CO₂H → R¹R²C•H + CO₂

Many ordinary alkyl radicals adopt nearly planar geometries and also have low barriers to configurational inversion. Consequently, the spatial information originally encoded in the tetrahedral stereogenic center can readily diminish. When the radical subsequently forms a bond with a nitrogen-containing reagent, the configuration of the product often cannot be transferred directly from that of the starting carboxylic acid.[1]

This distinction can be summarized as follows:

The dioxazolone system follows a different reaction sequence. The carboxylic acid first enters a polar two-electron pathway, followed by organized intramolecular rearrangements that accomplish skeletal transformation.[1]

2. The Reaction Begins with Carboxylate Attack on the Dioxazolone

2.1 The carboxylate is the nucleophilic species that initiates the reaction

The original study employed 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an organic base. Under the standard conditions, the carboxylic acid, dioxazolone, and DBU were reacted in dimethyl sulfoxide. Deprotonation of the carboxylic acid generates the carboxylate, which subsequently attacks the carbonyl group of the dioxazolone nucleophilically.[1]

This initial step was supported by both experimental and computational evidence.

Using cyclohexanecarboxylic acid as the model substrate, the authors carried out the following control experiments:

① In the absence of an external base, the neutral carboxylic acid produced essentially no desired product;

② When potassium cyclohexanecarboxylate was used directly, approximately 45% of the desired product was still obtained without an added base;

③ When the carboxylic acid was replaced with the corresponding methyl ester, no formation of the target amide was observed under the standard conditions.[1]

Density functional theory (DFT) calculations further showed that the initial nucleophilic addition of the carboxylate to the dioxazolone carbonyl has an activation free energy of 19.1 kcal/mol, consistent with the reaction proceeding under mild conditions.[1]

Together, these results support the following reaction entry pathway:

Carboxylic acid → Carboxylate → Nucleophilic addition to the dioxazolone

Decarboxylation occurs during the subsequent rearrangement steps.

3. From Dioxazolone to Hydroxamate: How the Two-Electron Pathway Proceeds

Based on control experiments and DFT calculations, the authors proposed a consecutive polar reaction pathway. For ease of understanding, this pathway can be condensed into three intermediate stages.[1]

3.1 Carboxylate addition and ring opening

The carboxylate attacks the carbonyl group of the dioxazolone, followed by C–O bond cleavage to generate the ring-opened intermediate Int1.

The proposed amide anion in Int1 then undergoes intramolecular nucleophilic addition to the carbonyl group, followed by a second C–O bond cleavage to afford the N,N-dicarbonyl-N-carbonate intermediate Int2.

Calculations indicate that both the second intramolecular nucleophilic addition and the subsequent C–O bond cleavage have relatively low activation barriers, suggesting that once Int1 is formed, its further conversion to Int2 is kinetically favorable.[1]

3.2 The first decarboxylation generates an N-hydroxy intermediate

Int2 subsequently releases CO₂ to form an important dicarbonyl N-hydroxy intermediate, Int3.

The authors specifically designed crossover substrate experiments to probe Int3. Two different substrate combinations—cyclohexanecarboxylic acid with methyl dioxazolone, and acetic acid with cyclohexyl dioxazolone—both converged to give the same N-cyclohexylacetamide product. This result is consistent with a mechanistic model in which both substrate combinations proceed through a common Int3 intermediate.[1]

The researchers also prepared a silyl-protected derivative of Int3. Deprotection generated Int3 in situ, after which formation of the target amide was observed, providing further experimental evidence for the involvement of Int3 in the reaction.[1]

3.3 Conversion of the N-hydroxy intermediate into a hydroxamate

Density functional theory calculations indicate that, after an appropriate conformational adjustment of the N-hydroxy intermediate Int3, its hydroxy oxygen can intramolecularly attack the acetyl carbonyl to form an oxaziridine-type intermediate, Int4. Int4 then undergoes rapid ring opening to generate the hydroxamate intermediate Int5.[1]

For the model system, the overall activation free energy from Int3 to the transition state leading to Int4 is 28.1 kcal/mol. On this basis, the authors regarded this process as the rate-determining step in the calculated reaction pathway. The activation free energy for ring opening of Int4 to form Int5 is only 4.7 kcal/mol, indicating that this ring-opening process is kinetically facile.[1]

The overall sequence can be summarized as follows:

Carboxylate

↓ Nucleophilic addition

Int1

↓ Intramolecular addition, C–O bond cleavage

Int2

↓ −CO₂

N-hydroxy intermediate Int3

↓ Intramolecular rearrangement

Hydroxamate intermediate Int5

Up to Int5, the reaction remains dominated by closed-shell polar intermediates and intramolecular rearrangements, without the involvement of a free carbon-centered radical.[1]

4. A Lossen-Type Rearrangement Transfers the Chiral Carbon Skeleton onto Nitrogen

4.1 The hydroxamate generates an alkyl isocyanate

DFT calculations support the subsequent Lossen-type rearrangement of Int5.

For the cyclohexyl model system used in the study, the calculated transformation is:

Hydroxamate Int5 → Cyclohexyl isocyanate (cHx–N=C=O) + Acetate

That is, the hydroxamate undergoes a 1,2-migration to form cyclohexyl isocyanate while simultaneously generating acetate. The calculated activation free energy for this step is 25.9 kcal/mol, and the transformation is strongly thermodynamically favorable.[1]

For a chiral carboxylic acid, this rearrangement has direct stereochemical significance. Let the organic group derived from the carboxylic acid be represented as R*:

R*–C(O)–NHOAc → R*–N=C=O

During the rearrangement, the carbon skeleton derived from the carboxylic acid migrates from the carbonyl carbon to nitrogen. The resulting isocyanate already contains the R*–N connectivity. At no point in the overall mechanistic model is R* required to first become a free R*• or R*⁺ species before forming a bond to nitrogen.[1]

This mode of migration provides a mechanistic basis for the transfer of the original stereochemical configuration.

4.2 The isocyanate is further converted into the final amide

The product of the Lossen-type rearrangement is not the final amide, but the corresponding alkyl isocyanate.

The authors proposed that the isocyanate generated in situ subsequently reacts with a carboxylate present in the reaction system and, through a Hofmann-type rearrangement-related process, releases another molecule of CO₂ to generate the final N-alkyl amide.[1]

The model reaction can be represented as:

R*–N=C=O + R³CO₂⁻ → R³C(O)NH–R* + CO₂

The overall structural transformation can therefore be summarized as:

R¹R²C*(H)–CO₂H

↓ Dioxazolone, DBU

R³C(O)NH–C*(H)R¹R²

Here, the chiral carbon skeleton derived from the carboxylic acid becomes the substituent on the amide nitrogen, while the acyl group carried by the dioxazolone constitutes the acyl portion of the final amide.[1]

5. Stereoretention Results from the Transfer of Configurational Information through Consecutive Rearrangements

The authors associated the high stereospecificity of this reaction with the absence of free carbon-centered radical and carbocation intermediates throughout the reaction pathway.[1]

The stereochemical differences between the two types of pathways can be summarized as follows:

Here, “stereoretention” means that the actual spatial relationship at the chiral carbon is retained before and after migration. The R/S descriptors before and after the reaction are not necessarily identical in every case, because conversion of the carboxyl group into a nitrogen-containing substituent can change substituent priorities under the Cahn–Ingold–Prelog rules. Therefore, when evaluating such transformations, the actual spatial configuration and changes in enantiomeric purity should be considered rather than judging stereochemical retention solely on whether the R/S descriptor remains unchanged.

6. Experimental Evidence Supporting the Two-Electron Rearrangement Mechanism

6.1 Radical probes do not show the expected ring-opening reaction

The authors investigated the decarboxylative amidation of cyclopropylacetic acid. If this substrate underwent single-electron decarboxylation to generate a cyclopropylmethyl radical, the resulting radical would be expected to undergo rapid ring opening. Experimentally, however, the resulting N-(cyclopropylmethyl)acetamide retained an intact cyclopropane ring, and the corresponding ring-opened product was not observed. This result is consistent with a mechanistic model in which the reaction proceeds predominantly through a two-electron pathway.[1]

In addition, carboxylic acid substrates containing carbon–chlorine bonds could also be converted successfully while retaining the C–Cl bond intact. In some radical reactions, C–Cl bonds can be cleaved through halogen atom abstraction. Therefore, preservation of this functional group provides additional evidence that free carbon-centered radicals are not the principal intermediates in this reaction.[1]

It should be noted that these two observations constitute experimental evidence supporting the two-electron pathway. The absence of cyclopropane ring opening or the retention of a C–Cl bond alone is not sufficient to exclude every possible radical process. The authors ultimately proposed the consecutive nucleophilic addition and rearrangement mechanism on the basis of the combined evidence from these substrate experiments, carboxylate control experiments, intermediate studies, and density functional theory calculations.[1]

6.2 The hydroxamate intermediate can be further converted into the target amide

The authors further investigated the proposed hydroxamate intermediate Int5-A. When this intermediate was subjected to the corresponding reaction conditions at an elevated temperature, formation of N-cyclohexylacetamide was observed. This result demonstrates that hydroxamate Int5-A can enter the subsequent product-forming pathway and is consistent with the proposed sequence of “hydroxamate → Lossen-type rearrangement → isocyanate → N-alkyl amide.”[1]

Taken together, the carboxylate control experiments, N-hydroxy intermediate experiments, hydroxamate validation experiments, and density functional theory calculations support the following major reaction sequence proposed by the authors:

Carboxylate nucleophilic addition → N-hydroxy intermediate → Hydroxamate intermediate → Lossen-type rearrangement → Isocyanate → N-alkyl amide

In this mechanistic model, the carbon skeleton derived from the carboxylic acid undergoes C–N bond formation through consecutive polar reactions and rearrangements, without requiring the key carbon center to first form a free carbon-centered radical or carbocation. This mode of reactivity also provides a mechanistic basis for the transfer of the original stereochemical configuration in chiral substrates.[1]

7. Experimental Results with Chiral Carboxylic Acids Are Consistent with a Stereoretentive Mechanism

The method was further applied to a range of chiral carboxylic acids, including substrates with stereogenic centers at benzylic positions as well as at more remote alkyl positions. Representative carboxylic acids with either cyclic or acyclic skeletons could be converted into the corresponding N-alkyl amides with high stereospecificity.[1]

Representative experimental results include:

① Ibuprofen can be converted into the corresponding chiral N-alkyl amide, with an enantiomeric ratio greater than 99:1;

② (S)-Naproxen and its brominated derivative both undergo stereoretentive decarboxylative amidation to generate the corresponding chiral N-alkyl amides;

③ The absolute configuration of the product derived from the brominated naproxen derivative was confirmed by single-crystal X-ray diffraction;

④ When the reaction of (S)-naproxen was conducted on a 10 mmol scale, the target product was obtained in 92% yield while maintaining an enantiomeric ratio greater than 99:1;

⑤ A chiral γ-amino acid derivative containing two stereocenters, as well as dihydroartemisinic acid, also participated in the reaction, with the corresponding products exhibiting diastereomeric ratios greater than 20:1.[1]

These results show that the stereochemical information carried by the starting carboxylic acids can be effectively transferred to the nitrogen-containing products during decarboxylative amidation. Combined with the mechanistic studies described above, this stereoretention is consistent with the reaction pathway proposed by the authors, involving carboxylate nucleophilic addition, consecutive rearrangements, and stereoretentive migration.[1]

It should also be noted that the degree of stereoretention can still be influenced by the specific substrate structure and reaction pathway. When the authors examined different dioxazolones using (S)-naproxen, the enantiomeric ratios of some products decreased. They proposed that this may be related to a certain degree of competitive formation of a decarboxylated carbanion from the secondary benzylic carboxylic acid.[1]

8. Further Optimization of the Reaction Conditions and Scale-Up Validation

Building on the earlier methodological and mechanistic studies, the same research team subsequently carried out further process optimization of this decarboxylative amidation reaction.[2]

The earlier study used dimethyl sulfoxide as the principal reaction solvent. In the subsequent study, the reaction medium was rescreened, and ethyl acetate was identified as an effective alternative solvent. The researchers also systematically investigated the effects of oxygen content, reaction concentration, water content, and temperature variations on the reaction outcome in order to evaluate the robustness of the optimized conditions under different operating conditions.[2]

On this basis, the authors performed scale-up experiments in the 5–50 mmol range and applied the optimized conditions to optically active carboxylic acids, including (S)-naproxen, further demonstrating the applicability of this stereoretentive decarboxylative amidation method at larger reaction scales.[2]

The two studies focused on different aspects of the reaction. The earlier study systematically examined substrate scope, stereochemical characteristics, and reaction mechanism, and proposed a reaction pathway centered on carboxylate nucleophilic addition and consecutive two-electron rearrangements. The subsequent study focused on solvent selection, tolerance toward operational variables, and scale-up validation.[1,2]

Accordingly, this reaction not only has a relatively well-defined mechanistic basis for stereoretention, but also has experimental support for extending the methodology from small-scale reactions to larger-scale synthetic conditions.

9. Reagents, Mechanistic-Study Substrates, and Representative Carboxylic Acid Products Related to Stereoretentive Decarboxylative Amidation with Dioxazolones

Table 1. Core Reaction Reagents and Reaction-Medium-Related Products

Table 2. Products Related to Mechanistic Studies and Model Reactions

Table 3. Products Related to Stereochemistry, Substrate Scope, and Complex Carboxylic Acid Scaffolds

Note: The products listed above are representative Aladdin products related to scientific research. Specific applications should be determined with reference to the product specifications, batch-specific COA, and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin website using the “product name/CAS/catalog number.”

References

[1] Kweon J, Park B, Kim D, Chang S. Decarboxylative stereoretentive C–N coupling by harnessing aminating reagent. Nature Communications, 2024, 15: 3788. DOI: 10.1038/s41467-024-48075-w.

[2] Kweon J, Lee M, Kim D, Chang S. Enhancing the Sustainability and Scalability of Transition-Metal-Free Stereoretentive Decarboxylative Amidation with Dioxazolones. Organic Process Research & Development, 2024, 28(9): 3691–3697. DOI: 10.1021/acs.oprd.4c00247.

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