Thermal-Mediated Synthesis of Hydantoin Derivatives from Amino Acids via Carbodiimide Reagents

Abstract

We introduce an innovative methodology for synthesizing hydantoins from amino acids using readily available carbodiimides, emphasizing the crucial role of temperature in the reaction process. This approach presents significant advantages over conventional methods involving isocyanates, facilitating easier handling and minimizing associated risks. Our strategy not only allows for the efficient production of a diverse array of hydantoin derivatives but also adheres to environmentally sustainable practices. The optimized reaction conditions enhance efficiency, marking a significant advancement in the field of organic synthesis. This method presents significant advantages for industrial applications, as it is a heat-mediated process that does not require the use of any bases or catalysts. By eliminating the need for additional reagents, this approach simplifies the reaction conditions, reduces potential side reactions, and minimizes the overall environmental impact. Additionally, the absence of catalysts streamlines the purification process, making it more cost-effective and efficient for large-scale production.

 

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Key word

hydantoin - carbodiimide - amino acid - urea - N-heterocyclic organic compound

The chemistry and properties of hydantoins and their derivatives have received significant attention for over 150 years due to their versatile medicinal and industrial applications. Hydantoin is a five-membered heterocyclic compound that contains two nitrogen centers and two carbonyl groups. In synthetic organic chemistry, all positions within the hydantoin ring are chemically active, facilitating straightforward derivatization through reactions with various nucleophiles or electrophiles. This reactivity enables the synthesis of a diverse array of molecular structures, including alkylidene hydantoins, fused hydantoins, and spiro hydantoins.[1] [2]

The hydantoin structure is found in numerous commercially available drugs and serves as the foundation for many drug candidates currently under investigation. Compounds featuring the hydantoin skeleton exhibit a wide range of biological activities, including antimicrobial, antitubercular, antitumor, antiviral, antioxidant, anti-inflammatory, antifungal, antimalarial, antidepressant, antidiabetic, anti-Alzheimer, and antibacterial properties. Thus, the increasing interest in these structures from both synthetic and pharmacological viewpoints is well justified (Figure [1]).[3]

Figure 1 Examples of drugs containing the hydantoin structure

Hydantoins are not only commonly used in the pharmaceutical field, but they also serve as catalysts, chiral auxiliaries, and reagents in the synthesis of natural products and organic compounds.[4] [5] In addition to their synthetic production, hydantoins occur naturally in living organisms, primarily within marine organisms and bacteria.[6,7]

The rich chemistry of carbodiimides has attracted increasing interest from chemists, positioning these molecules as significant in modern organic chemistry, especially in the synthesis of N-heterocycles.[8] These compounds are essential in peptide and polyurethane synthesis and play vital roles in cross-linking reactions. Additionally, carbodiimides are employed in various reactions, including nickel-catalyzed amidation and hydrazide coupling. Recent studies from our group have utilized carbodiimides in amidation reactions of secondary amines with non-steroidal anti-inflammatory drugs such as ibuprofen, ketoprofen, and naproxen, as well as in the direct amidation of unactivated carboxylic acids.[9] [10]

In recent years, there has been extensive research on the structural modification of hydantoins and their derivatives in both industry and academia. Currently, many research groups are focusing their efforts on developing simple, rapid, convenient, and environmentally friendly methods for producing various substituted hydantoins and thiohydantoins. Hydantoins can be viewed as cyclic urea structures derived from amino acids, and due to this close relationship, they can primarily be prepared from the corresponding amino acids. There are three main synthetic pathways known for the preparation of hydantoins (Scheme [1]).[6] The Bucherer–Bergs method[11] synthesizes hydantoins by reacting carbonyl compounds or cyanohydrins with ammonium carbonate and potassium cyanide in various solvents or solvent-free conditions, while the Biltz method[12] uses 1,2-diketones and urea under similar conditions, and the Read method[2] [13] involves cyclizing urea derivatives from amino acids or aminonitriles with cyanates or isocyanates in acidic or basic environments. The first two classical methods for hydantoin synthesis, the Bucherer–Bergs and Biltz methods, are based on the reactions of carbonyl or dicarbonyl compounds that yield racemic hydantoins. In contrast, the Read conditions involve a two-step enantioselective condensation–cyclization of amino acid derivatives in the presence of isocyanates. However, these isocyanates are often not commercially available, and their synthesis typically requires multi-step reactions with toxic reagents. The challenging reaction conditions, limited availability of starting materials, long reaction times, issues with reagent solubility, low yields, and environmental concerns strongly limit the potential of traditional synthetic methodologies. Consequently, there is a growing effort towards more environmentally friendly and user-friendly approaches, particularly those based on amino acid derivatives.[14]

A great deal of research has been conducted to investigate various methodologies for the synthesis of hydantoins. McElwee-White and co-workers employed W(CO)₆ as a catalyst, but their method was constrained by steric hindrance affecting yields,[15a] while the Cuny group utilized triphosgene and faced significant challenges related to toxicity and the need for multistep synthesis.[15b] Pan and co-workers implemented Tf₂O and pyridine, requiring additional activation steps for amino acids,[16a] and Declas and co-workers investigated cyanobenziodoxolone (CBX), which depended on expensive reagents.[16b] Colacino and co-workers reported a mechanochemical synthesis that raised concerns about the control of reaction conditions.[17] However, the same group later introduced a relatively environmentally benign one-pot synthesis that effectively produced 5- and 5,5-disubstituted hydantoins (Scheme [1]).[5]

Scheme 1 Methods for the synthesis of hydantoins

New synthetic approaches for hydantoin synthesis are crucial for sustainability and minimizing environmental impact. Traditional methods often rely on unstable isocyanates, which present challenges such as multistep syntheses and polymerization. In contrast, our methodology employs commercially available carbodiimides, which are more stable, easier to handle, and can be stored under milder conditions, facilitating straightforward access to various derivatives. In our previous work, we introduced an innovative and efficient amidation method that functions without the need for catalysts or activators, facilitating the direct amidation of carboxylic acids with carbodiimides.[10] Interestingly, we found that when amino acids were employed as substrates instead of carboxylic acids, the reaction produced hydantoin structures rather than the anticipated amidation products (Scheme [2]).

Scheme 2 Synthetic scheme of hydantoin

To enhance overall reaction efficiency, optimization experiments were conducted through systematic adjustments of various reaction parameters, including the choice of base, temperature, and solvent (Table [1]). In the model reaction, phenylalanine was reacted with N,N′-diisopropylcarbodiimide (DIC) in acetonitrile at 60 °C with pyrrolidine as the base, resulting in a moderate yield of 43%, which is deemed satisfactory for an initial assessment. Although the results of the solvent screenings did not reveal significant differences, the highest reaction yield was observed in dioxane. After observing nearly similar reaction yields with various bases, it became evident that temperature plays a significantly more crucial role in the reaction. Notably, conducting the reaction at 80 °C without the use of a base resulted in an excellent yield, as anticipated. As expected, despite prolonged reaction times, only trace amounts of conversion were observed at room temperature, and a low yield of merely 12% was obtained at 50 °C.

Table 1 Optimization of the Reaction Conditions^a

Entry	Solvent	Base	Temp (°C)	Yield (%)b
1	CH3CN	pyrrolidine	60	43
2	H2O	pyrrolidine	60	10
3	toluene	pyrrolidine	60	55
4	DMSO	pyrrolidine	60	35
5	dioxane	pyrrolidine	60	57
6	dioxane	Et3N	60	61
7	dioxane	DIPA	60	63
8	dioxane	Na2CO3	60	55
9	dioxane	–	80	98
10c	dioxane	–	50	12
11c	dioxane	–	rt	trace

^a The reaction was performed with 1a (0.3 mmol), 2a (1.2 equiv), and 2.0 mL of solvent for 4 h.

^b Isolated yields.

^c The reaction was continued for 16 h.

Under optimized conditions, a series of amino acids 1a–k were reacted with DCC (N,N′-dicyclohexylcarbodiimide) and DIC carbodiimides 2a,b, yielding the corresponding hydantoins 3a–y (Scheme [3]). We were surprised to find that most amino acids, with the exception of a few specific ones such as phenylalanine (1a), isoleucine (1d), methionine (1g), and 2-aminobutyric acid (1h), exhibited very low yields. Our prior optimization studies indicated that reaction conversion was predominantly temperature-dependent, prompting us to apply an alternative method for substrates with low yields. Significantly, we observed marked increases in reaction conversions when the reaction time was extended from 4 h to 9 h under reflux conditions. For instance, valine (1c yielded the related hydantoins 3e,f in a yield of 52% and 35% under conditions A with DCC and DIC, respectively; however, these yields improved remarkably to 92% and 89% under modified conditions B. Similarly, alanine’s yields increased from 25% (3i) and 27% (3j) with the initial conditions to over 90% with the revised approach. In the case of glycine, solubility issues resulted in low yields of 15% (3k) and 18% (3l) under conditions A; however, the cyclization reaction using DCC and DIC yielded impressive yields of 91% (3k) and 95% (3l), respectively, under modified conditions B. Conversely, no product formation (3r–u) was observed for phenyl glycine 1i and tert-leucine 1j when reacted with DCC and DIC, even after 16 h, likely due to steric hindrance. These results underscore the importance of optimizing both reaction conditions and time to enhance yields, particularly for substrates that initially demonstrate low conversion rates. Hydantoins synthesized from reactions involving isoleucine with DCC and DIC exhibited diastereomeric ratios of 1:1, indicating that both diastereomers were formed in a stable and reproducible manner during the synthesis. This finding suggests that the reaction conditions effectively promote the equal formation of both isomers, highlighting the significant influence of steric and electronic factors within the reaction mechanism. Furthermore, the molecular structure of compound 3b was fully elucidated through single-crystal X-ray crystallography, confirming its structural integrity (Figure S1). To evaluate the efficiency of the reaction on a gram scale, an impressive NMR yield of approximately 99% for compound 3a was achieved from the reaction of 1 g of phenylalanine (1a) with DIC (2a), using 1,4-dimethoxybenzene as an internal standard for precise quantification. This remarkable yield underscores the robustness and scalability of the developed methodology. The data support that the reaction conditions are optimized for high-yield synthesis and suggest the potential applicability of this method for larger-scale synthesis, including industrial production. The consistency and reproducibility of these results highlight the methodology’s effectiveness for upscaling without compromising the yield or purity of the product.

Scheme 3 Substrate scope. Conditions A: 1 (0.3 mmol), 2 (1.2 equiv), and 2.0 mL dioxane at 80 ℃ for 4 h. Conditions B: 1 (0.3 mmol), 2 (1.2 equiv), and 2.0 mL dioxane at 100 ℃ for 9 h.

In the direct amidation of carboxylic acids with carbodiimides, the proposed mechanism posits that the formation of hydantoins occurs via isocyanates that may form during the reaction (Scheme [4]).[17] Initially, the reaction between amino acid 1 and carbodiimide 2 yields the O-acyl urea ester 6. This intermediate then undergoes an intramolecular nucleophilic attack at the carbonyl center, resulting in the formation of a four-membered ring intermediate 7. Subsequently, the rearrangement of the carbonyl group facilitates the sequential cleavage of the C–O and C–N bonds, producing the amide product 9 and the isocyanate byproduct 8. It is expected that the generated isocyanate will interact with the amino acid derivative 9 to form intermediate 10, which, upon further rearrangement, will yield the target product, hydantoin 3, alongside the byproduct amine 12. This mechanistic pathway underscores the complex interactions between reaction intermediates and their transformations, ultimately resulting in the formation of the desired hydantoin derivatives.

Scheme 4 Proposed reaction mechanism

In conclusion, our novel methodology for synthesizing hydantoins from amino acids using carbodiimides represents a significant advancement in organic synthesis.[18] By highlighting the essential role of temperature in optimizing reaction conditions, we provide a safer and more efficient alternative to traditional isocyanate methods. This approach not only streamlines the production of a wide variety of hydantoin derivatives but also aligns with environmentally sustainable practices. Our findings underscore the potential for this methodology to be adopted in both academic and industrial settings, paving the way for further innovations in the synthesis of valuable chemical compounds.

 

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Conflict of Interest

The authors declare no conflict of interest.

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• 18 General Procedure A Amino acid (0.3 mmol) and carbodiimide (1.2 equiv) were stirred in 2 mL of dioxane at 80 °C for 4 h. Then, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM/EtOAc as the eluent. General Procedure B A solution of the amino acid (0.3 mmol) and carbodiimide (1.2 equiv) in dioxane (2 mL) was refluxed (100 °C) for 9 h. Then, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM/EtOAc as the eluent.

Publication History

Received: 04 January 2025

Accepted after revision: 22 January 2025

Accepted Manuscript online:
22 January 2025

Article published online:
12 March 2025