Interception of RCONCl₂: late-stage hydrolysis and esterification of primary amides

Abstract

Current strategies for activating amides primarily focus on secondary or tertiary amides. However, the activation of primary amides, the simplest form of amides, remains a significant challenge. In this study, we propose a novel approach that involves generating and intercepting RCONCl₂in situ to activate primary amides under mild conditions. This method allows for hydrolysis and esterification of primary amides without the use of strong Lewis acid or transition-metal catalysts typically used in amide activation. We demonstrate the synthetic potential of this approach through late-stage modifications on complex molecules, tolerance toward over 20 heterocycles, and scalability. Mechanistic experiments and DFT calculations suggest that the formation of RCONCl₂ and subsequent nucleophilic attack with hydrogen bonding assistance play crucial roles in this transformation.

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Introduction

Amide bonds are crucial structures commonly found in bioactive molecules, natural products, drugs, polymers, and functional materials.¹ However, despite their significance and prevalence, the chemical community often overlooks them as synthetic modules. This is because amides have lower reactivity compared to other carboxylic acid derivatives like acyl halides, anhydrides, and acids due to amidic resonance (RE = 15–20 kcal mol⁻¹ in planar amides), which is explained in basic organic chemistry textbooks. Consequently, there has been a historical perception that amides are too inert to be used as acylation reagents.

Despite the formidable challenges, recent years have seen significant success in C(O)–N bond activation. This has greatly expanded the toolkit available to chemists, allowing them to utilize the synthetic potential of typically inert amides. Since Ghosez's pioneering work,² the use of trifluoromethanesulfonic anhydride for amide electrophilic activation has become a powerful tool in synthetic chemistry (Fig. 1a).³ This is thanks to significant contributions from Huang,⁴ Maulide,⁵ and other research groups.⁶ Furthermore, there have been recent conceptual advancements in amide C(O)–N bond activation from the groups of Garg,⁷ Szostak,⁸ and Zou.⁹ Through a ground-state destabilization strategy, twisted amides were used as electrophiles (Fig. 1b) to obtain acylation or decarbonylation products under transition-metal or transition-metal-free reaction conditions.¹⁰ Both electrophilic activation and ground-state destabilization of amides have now become mainstream techniques in synthetic chemistry. These methods enable the transformation of inert amide bonds into functional groups that can be modified, facilitating a wide range of previously challenging reactions.

Fig. 1 Activation strategies for amides. (a) Electrophilic activation of secondary or tertiary amide. (b) Ground-state destabilization of twisted amides. (c) This work: Direct transformation of primary amides via RCONCl₂.

Despite progress in the field, research on amide activation lags behind that of other carboxylic acid derivatives. The chemical community is actively seeking novel activation strategies to overcome existing challenges. Compared to secondary and tertiary amides, the activation of primary amides has barely been explored and remains a huge challenge. Primary amides, unlike secondary and tertiary amides, cannot react with trifluoromethanesulfonic anhydride to form the required iminium intermediate due to the weak Lewis basicity of their oxygen atoms. Therefore, electrophilic activation is not suitable for primary amides. While ground-state destabilization has proven successful with sterically twisted tertiary amides, achieving geometric alterations in primary amides is difficult. Twisted tertiary amides are not commercially available and often require pre-synthesis from primary or secondary amides, which can be time-consuming and inefficient in terms of atom usage. In contrast, primary amides are readily available as commercial feedstock chemicals (with nearly 100 000 options) or can be easily prepared from various carboxylic acids with diverse structures. Therefore, directly transforming primary amides bearing diverse structures not only provides a powerful method for acyl transfer but also holds significant potential to impact amide chemistry and contribute to drug discovery efforts.

In order to enhance the versatility of primary amides as a synthetic module, we propose a unique method to weaken their planar resonance. Our hypothesis is that the electron-withdrawing nature of chlorine atoms allows for predictable activation of amides by reducing planar resonance (Fig. 1c). Furthermore, the small size of chlorine can facilitate attack on RCONCl₂ by nucleophiles. By using this strategy, a mild approach for hydrolysis and esterification reactions of both aromatic and aliphatic primary amides has been successfully developed. This innovative approach offers several distinct advantages such as late-stage modification, transition-metal-free conditions, resistance to air and moisture, broad substrate compatibility, and operational simplicity.

Results and discussion

Initially, we performed preliminary theoretical calculations to test our hypothesis. We used the COSNAR method developed by Greenberg et al.¹¹ to calculate the resonance energy of the amide bond in PhCONH₂ and PhCONCl₂. The calculated values were 19.7 kcal mol⁻¹ for PhCONH₂ and 4.5 kcal mol⁻¹ for PhCONCl₂ (Fig. 2a). These results indicate a significant weakening of the C(O)–N bond in PhCONCl₂, which could enhance nucleophilic attack on the carbonyl group. A similar outcome can be achieved through an isodesmic reaction as shown in Fig. 2b.

Fig. 2 DFT calculations on the effect of chlorine atoms.

Our hypothesis was that RCONCl₂, with weakened planar resonance, is more reactive than RCONH₂ in nucleophilic substitution reactions. This is the key to the success of our designed scenario, which we intend to verify with hydrolysis reactions. Hydrolysis of primary amides is typically unfavorable both thermodynamically and kinetically, requiring harsh conditions such as strong acids/bases and high temperatures.¹² In 2020, Garg and coworkers developed a one-pot, two-step hydrolysis strategy, in which 2-(trimethylsilyl)ethanol was used for nickel-catalyzed esterification followed by fluoride-promoted deprotection to generate the corresponding carboxylic acid.¹³ We conducted hydrolysis experiments on RCONCl₂ and RCONH₂.¹⁴ As anticipated, the experimental findings showed that RCONCl₂ exhibited higher reactivity compared to RCONH₂, albeit with low yields (Fig. 3). These results effectively demonstrate the viability of our concept: by introducing chlorine atoms, we can greatly reduce the planar resonance of amides and transform them into acylating agents with significant synthetic potential.

Fig. 3 Initial hydrolysis test.

Although the initial experimental results mentioned above show great promise, there were still significant challenges to overcome in activating primary amides. Chlorinating reagents often lead to chlorination or oxidation of nucleophiles (water or alcohol).¹⁵ Hence, it is crucial to identify a suitable chlorinating reagent that reacts preferably with primary amides to obtain RCONCl₂, rather than causing undesired side reactions with nucleophiles. Additionally, the identified chlorinating reagents should react quickly and cleanly with primary amides, eliminating the need for further purification. The resulting RCONCl₂ can then undergo smooth nucleophilic substitution to produce the desired products.

After testing various chlorinating reagents, we found tert-butyl hypochlorite to be the most effective option for hydrolysis of primary amides. By mixing p-chlorobenzamide and tert-butyl hypochlorite in acetone/H₂O at room temperature for 24 hours, we achieved a high yield of 99% for the desired acid 2b (Table S1, entry 1 in ESI†). Hydrolysis reactions of amides are known to be extremely slow, with a half-life of several hundred years.¹⁶ However, by generating and intercepting RCONCl₂in situ, we successfully established a mild hydrolysis method for primary amides under neutral conditions. It is important to note that other commercially available chlorinating reagents yielded inferior results (Table S1, entries 2–4†), and that changing the solvent type also resulted in poorer product formation outcomes (Table S1, entries 5–15†). One notable advantage of this reaction setup is its simplicity; it does not require air removal or the use of metal catalysts.

After developing a practical protocol, we assessed its generality for primary amides. Scheme 1 demonstrates that the optimized reaction conditions successfully tolerated a wide range of common functional groups, including halide (2b, 2c, 2e, 2k, 2o–2q), alkyl (2f and 2g), carboxyl (2l), sulfone (2h), CF₃ (2i, 2j, 2n, 2p) and nitro (2d and 2o). Notably, a tertiary amide (2x) was also compatible with this system. Oxidizable functional groups such as free hydroxyl groups (2aa) and easily hydrolyzable groups, such as ester (2w), BocO (2m), and TsO (2t), could be preserved during the reaction. Encouragingly, positional changes in ortho-, meta-, or para-substituents on aromatic amides did not impact the reaction outcomes. Desired carboxylic acids were obtained in good to nearly quantitative yields regardless of these substitutions. Compared to aromatic amides containing electron-withdrawing groups, those with electron-donating groups had lower activity and required heating conditions for efficient hydrolysis (2f and 2g). This indicates that the rate-determining step for these hydrolysis reactions is nucleophilic attack by water on RCONCl₂. We then focused on the hydrolysis of aliphatic amides, which are typically considered unreactive in twisted amide activation reactions due to their resistance to oxidative addition with transition-metal catalysts.^10y This transition-metal-free approach was expected to work for both aromatic and aliphatic amides. Various structurally diverse aliphatic amides (2m, 2t, 2v–2x) were treated with standard reaction conditions, resulting in high yields of the desired carboxylic acids.

Scheme 1 Scope of amides for hydrolysis. Reaction conditions: amide (0.5 mmol), tert-butyl hypochlorite (4.0 equiv.), acetone/H₂O (2.0 mL/2.0 mL), under air at 25 °C for 24 h. Isolated yield. ^a40 °C. ^btert-Butyl hypochlorite (6.0 equiv.).

Heterocycles are commonly found in biologically active molecules, pharmaceuticals, agrochemicals, and advanced materials. A limitation of transition metal-catalyzed amide activations is their reduced feasibility for substrates bearing heterocycles due to the poisoning of transition metal catalyst. Fortunately, our hydrolysis system was found to be compatible with various medicinally relevant heterocycles such as thiazole (2u), pyridine (2ac), pyrrolidin-2-one (2x), phthalimide (2v), 1,2,3-triazole (2z), and 1,2,4-triazole (2aa). Amide hydrolysis is a crucial step in the synthesis of drug molecules and complex products.¹⁷ However, it typically requires strong acids or bases. Our methodology offers excellent functional group compatibility and mild reaction conditions, making it suitable for late-stage modification of complex molecules. As expected, dinitolmide, an approved anticoccidial agent, yielded the desired product 2y almost quantitatively. Highly functionalized drug molecules like rufinamide (2z) with a 1,2,3-triazole moiety and ribavirin (2aa) with a 1,2,4-triazole moiety were both converted into the corresponding acids with excellent yields. Probenecid, an antipodagrics compound bearing a tertiary sulfonamide group, also smoothly reacted to produce the desired product 2ab in a yield of 93%. Considering the ease of further transforming carboxylic acids, we believe this hydrolysis methodology will enhance the toolkit for drug discovery programs exploring these pharmacophores. To demonstrate the robustness of this methodology further, we scaled up the amide hydrolysis using 4-chlorobenzamide as the raw material. Without modifying the original protocol, we successfully transformed 10 mmol of 4-chlorobenzamide into product 2b without any significant decrease in yield.

Both secondary amide (N-methylbenzamide) and tertiary amide (N,N-dimethylbenzamide) were found to be unsuitable substrates for the hydrolysis process. The Winkler–Dunitz parameters (τ + χ_N) are often used to describe the geometric distortion of amides, which can predict the reactivity of twisted amides. Calculations show that PhCONCl₂ (Fig. 4) has less distortion compared to classical twisted amides like N,N-Boc₂-benzamide¹⁸ and N-benzoyl-glutarimide.¹⁹ However, despite this higher distortion, the expected hydrolysis reaction did not occur in the case of twisted amides. We also tested Weinreb amide,²⁰ a commonly used acylation reagent. Surprisingly, it did not undergo hydrolysis; instead, most starting materials were recovered. These results clearly demonstrate our approach offers a complementary and fundamentally distinct strategy for activating amides, which may be due to the significant pyramidalization of nitrogen atom and small size of the chlorine atom.

Fig. 4 The geometric distortion of PhCONCl₂.

The activity of carboxylic esters is generally higher than that of amides. Therefore, the esterification of amides typically requires harsh reaction conditions such as strong acidity or basicity, toxic reagents, high temperatures, and/or large amounts of alcohol solvents.²¹ Since the pioneering work from the group of Garg,⁷ a series of esterification methods for twisted amides^10y,22 have been successfully developed under transition-metal or metal-free conditions. However, these methods are mainly applicable to aromatic tertiary amides. Building on the success achieved in hydrolysis reactions, we aimed to extend this strategy to other nucleophilic substitution reactions of amides. Interestingly, although hydrolysis and esterification share similar elementary steps, there is currently no general method that can be applied to both processes. We were excited to find that this innovative activation strategy can be used not only for amide hydrolysis, but also for achieving amide esterification under mild conditions. By intercepting RCONCl₂ with alcohols, both aromatic and aliphatic amides can effectively function as acylating agents, resulting in high yields of the desired ester products.

At the outset, a systematic survey of esterification reaction conditions was carried out using amide 3a and alcohol 4a as model substrates (for more information on reaction optimization, see Table S2 in the ESI†). The reaction was performed in cyclohexane with TCCA (trichloroisocyanuric acid) as the chlorinating reagent and PhCOOLi as the base. This resulted in the successful synthesis of desired ester 5a, with an impressive yield of 87%. With the optimal conditions in hand, the scope of amides in this process was investigated (Scheme 2). Remarkably, the esterification reaction exhibited a wide range of functional group tolerance; various groups such as halide (5a, 5c, 5d, 5n, 5s–5u), NO₂ (5e and 5n), CF₃ (5m), carbonyl (5i), ester (5j and 5u), ether (5k), and benzyl chloride (5h), remained unaffected under these mild reaction conditions. Pentafluorobenzamide (5l) proved to be a suitable substrate for this protocol. Both trichloroacetamide (5s) and dichloroacetamide (5t) yielded desired esters with satisfactory yields. It is worth noting that this esterification system is compatible with both biologically relevant carbon rings such as cyclopentane 5q and naphthalene 5r, as well as heterocycles like isoxazole 5o and benzofuran 5p. As expected, when ethyl oxamate was used as a reactant, the desired ester 5u was obtained with a yield of 79%. Not surprisingly, secondary amide, tertiary amide, twisted amides, and the Weinreb amide were found to be unreactive under these conditions.

Scheme 2 Scope of amides for esterification. Reaction conditions: amides 3 (0.2 mmol), alcohol 4a (2.0 equiv.), TCCA (2.0 equiv.), PhCOOLi (2.5 equiv.), cyclohexane (2.0 mL), under air at 25 °C for 1 h, then 40 °C for 48 h. Isolated yield. ^a 25 °C for 1 h, then 60 °C for 48 h.

After defining the scope of primary amides, we evaluated the generality of the alcohols (Scheme 3). Methanol (5v) and butanol (5w) smoothly produced esters with high yields. A major limitation of current amide alcoholysis is its compatibility only with simple alcohols.^21,22 In this study, a wide range of structurally diverse alcohols were successfully converted to valuable functionalized esters by intercepting RCONCl₂. This demonstrated an extensive tolerance for different functional groups, including alkyl halides (5x, 5an, 5as, and 5ax), aryl halides (5aa–5ac), CF₃ (5ad and 5bd), carbonate (5bb), Boc (5am, 5ap, 5az and 5bc), ketal (5ag), phosphate (5af), silyl (5ah and 5ar), ketone (5ak), ester (5be), ether (5y), tertiary alcohol (5aq), and epoxide (5ai and 5aj) groups which remained unaffected in the reaction. Primary amides are often used as nucleophiles to form C–N bonds by replacing the hydroxy group of benzyl alcohols.²³ However, in this study, benzyl alcohols were unexpectedly found to be suitable nucleophiles instead of electrophiles. As a result, desired benzyl esters (5z, 5aa, 5ac–5ae) were obtained with high yields. It is worth mentioning that when secondary alcohols were used as reactants, moderate yields of the corresponding esters (5bc–5bg) were also obtained. Additionally, under these mild esterification conditions, optically pure substrates (5am, 5az, and 5be) were converted into corresponding esters without changing their configuration. This advantage is expected to benefit the application of this method in chiral drug discovery.

Scheme 3 Scope of alcohols for esterification. Amides (0.2 mmol), alcohols (2.0 equiv.), TCCA (2.0 equiv.), PhCOOLi (2.5 equiv.), cyclohexane (2.0 mL), under air at 25 °C for 1 h, then 40 °C for 48 h. Isolated yield. ^a25 °C for 1 h, then 60 °C for 48 h.

Given the prevalence of cyclic scaffolds in drugs and agrochemicals, we conducted experiments to assess the efficacy of various alcohols in synthesizing esters with different carbo- and heterocyclic scaffolds. This transformation readily accommodated carbocyclic compounds like cyclobutane (5bf), cyclopentane (5bg), and adamantane (5at). Heterocyclic compounds containing oxygen atoms such as oxetane (5aj), tetrahydrofuran (5ai), 1,3-dioxolane (5ag), and 1,3-dioxolan-2-one (5bb)—common motifs in drug scaffolds—also underwent efficient esterification. Medicinally relevant nitrogen heterocycles including pyridine (5y and 5ao), pyrrolidine (5am), piperidine (5ap), azetidine (5bc), and succinimide (5au and 5ba) successfully delivered the desired esters with good to excellent efficiency. Multiple-nitrogen-heterocycles such as pyrimidine (5ay), pyrazine (5av), and benzotriazole (5al) were also converted into corresponding esters with high yields.

In order to further demonstrate the effectiveness of our novel strategy, we next conducted late-stage modifications of complex molecules or drug scaffolds. As shown in Scheme 4, primary amides progenitors of nicotinamid (5bh), aspirin (5bi), rufinamide (5bj), temozolomide (5bk), fenofibric acid (5bl), UV absorber THUV-328 (5bm), dinitolmide (5bn), and probenecid (5bo) were subjected to our mild conditions, generating the corresponding esters in moderate to excellent yields. We also tested a variety of structurally diverse alcohols for this transformation. For instance, diacetonefructose (5bp) and diacetonegalactose (5bt and 5bw) both delivered the desired esters with satisfactory yields. Cyclandelate (5bq), an α-hydroxy ester, was smoothly converted into its corresponding ester with excellent yield. Esterification of the primary alcohols in menthone (5br and 5bu) delivered the corresponding esters in high yields. When using icaridine as the alcohol source, high yields of the desired ester 5bs and 5bv were achieved. These findings demonstrate both the practicality and versatility of our innovative amide activation strategy, which can accommodate a wide range of pharmaceutically relevant functional groups including heterocycles, sulfonamides, aryl bromides, and more.

Scheme 4 Late-stage modification on complex molecules. Reaction conditions: amides (0.2 mmol), alcohols (2.0 equiv.), TCCA (2.0 equiv.), PhCOOLi (2.5 equiv.), cyclohexane (2.0 mL), under air at 25 °C for 1 h, then 40 °C for 48 h. Isolated yield. ^a25 °C for 1 h, then 60 °C for 48 h.

During the hydrolysis of amides, the presence of RCONCl₂ was detected. Under standard conditions, RCONCl₂ can be efficiently converted into a carboxylic acid in nearly quantitative yield (Fig. 5a). When RCONCl₂ and RCONH₂ were separately reacted under standard conditions for one hour (Fig. 5b), it was observed that the conversion rate of RCONCl₂ was significantly higher than that of RCONH₂. Based on these results, we conclude that RCONCl₂ serves as an intermediate product in the hydrolysis of amides. The competition experiment demonstrates that electron-withdrawing groups are more favorable for the hydrolysis of amides (Fig. 5c). This indicates that the nucleophilic attack of water molecules on RCONCl₂ is the rate-determining step of this process.

Fig. 5 Preliminary mechanistic study.

Computational studies were performed to shed light on the hydrolysis mechanism of PhCONCl₂ (Fig. 6). When a single water molecule attacks the carbonyl carbon of PhCONCl₂ to undergo hydrolysis, the predicted activation barrier, however, is very high (for details, see Fig. S1 in ESI†). The presence of more water molecules might stabilize the leaving group (–NCl₂) via a H-bonding interaction, and hence could assist the hydrolysis of PhCONCl₂. Computational results suggest that the activation energy would be lowered significantly (24.2 kcal mol⁻¹) when five water molecules are involved in the hydrolysis of PhCONCl₂ (for hydrolysis involving two-four water molecules, see Fig. S2–S4 in ESI†).

Fig. 6 Energy profile (in kcal mol⁻¹) for the hydrolysis of primary amides.

Conclusions

Through the interception of RCONCl₂, we have developed a mechanistically distinct and versatile method for activating primary amides. This protocol allows the conversion of various types of primary amides, including aromatic and aliphatic ones, into acids or esters under metal-free conditions. It uses commercially available primary amides as the source of acyl, greatly simplifying operations, shortening the synthetic sequence, and enhancing overall efficiency in atom utilization. It can tolerate over 20 heterocycles and nearly all common functional groups. Furthermore, we demonstrate the synthetic potential of this approach by performing late-stage modifications of complex products and drug-like molecules. Mechanistic investigation and DFT calculations suggest that this transformation involves the generation of RCONCl₂ followed by nucleophilic attack facilitated by hydrogen bonding.

Data availability

Full experimental results are available in the ESI.†

Author contributions

X. Wan and X.B. conceived and supervised the project. X.W., J.B., J.L., Z.C. and M.L. performed the experiments and developed the reactions. J.L. and K.W. performed the DFT calculations for the mechanistic studies. X. Wan wrote the manuscript with feedback from all authors. All authors analyzed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), NSFC (grant numbers 21973068, 21971175).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data, and NMR spectra. See DOI: https://doi.org/10.1039/d3qo01730c

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