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. 2025 Aug 28;10(35):40658–40667. doi: 10.1021/acsomega.5c07709

Reactions of Nitrile Imines with Thiohydantoin Derivatives: Unexpected Chemoselectivity of the 1,3-Dipolar Cycloaddition: Preferential Addition of C=C rather than C=S Bonds

Maria E Filkina a, Egor A Zhukov a, Victor A Tafeenko a, Artem V Semykin a, Maxim E Kukushkin a, Mikhail S Nechaev a,b, Elena K Beloglazkina a,*
PMCID: PMC12423912  PMID: 40949292

Abstract

Nitrile imines are highly reactive 1,3-dipoles that have found extensive application in [3 + 2]-cycloaddition reactions, offering an efficient approach to introducing pyrazoline and pyrazole motifs into biologically active compounds. In this study, we explore the reactivity of nitrile imines using thiohydantoin derivatives as dipolarophiles, which feature both carbon–carbon and carbon–sulfur bonds suitable for cycloaddition. Typically, carbon–sulfur (C=S) bonds are considered “super dipolarophiles” in nitrile imine cycloaddition reactions. However, we observed an unexpected chemoselectivity in the reaction between nitrile imines and 5-methylidene-2-thiohydantoin, where the reaction surprisingly favored the carbon–carbon (C=C) bond over the expected carbon–sulfur (C=S) bond. Our findings demonstrate that the electronic effects of substituents play a crucial role in determining the reactivity and selectivity of nitrile imines. Specifically, electron-withdrawing groups enhance the reactivity and favor cycloaddition at C=S bonds in thiohydantoins, whereas electron-donating groups or halogens facilitate cycloaddition at C=C bonds. To gain a deeper understanding of the reaction mechanisms and chemoselectivity, we performed density functional theory (DFT) calculations. This work provides a detailed understanding of the factors influencing 1,3-dipolar cycloaddition reactions of nitrile imines, highlighting how electronic effects influence their behavior.

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Introduction

The 1,3-dipolar cycloaddition reaction is one of the most efficient methods for the synthesis of five-membered heterocyclic systems. Among the 1,3-dipoles, nitrile imines are widely used as convenient building blocks for the pyrazoline and pyrazole derivative preparations. , Both pyrazoline/pyrazole and spiropyrazoline scaffolds are featured in a number of natural and synthetic products with a wide range of biological activity. − Nitrile imines are known for their ability to participate in cycloaddition reactions involving multiple bonds, specifically carbon–sulfur, carbon–nitrogen, and, in rare cases, carbon–oxygen. , The cycloaddition of nitrile imines to exocyclic carbon–carbon and carbon–heteroatom bonds facilitates the straightforward access to the structures featuring spirocarbon fragments.

The reactivity of nitrile imines (NI) in their interaction with dipolarophiles is determined both by steric and electronic effects and may be effectively rationalized by frontier molecular orbital (FMO) theory. Nitrile imines are considered to be “type II” dipoles, which means that interactions between both the HOMOdipole and the LUMOdipolarophile and the interactions of the HOMOdipolarophile and LUMOdipole may have an impact on the reaction rate. Substitution of the nitrile imine with different functional groups can significantly change its reactivity profile. Specifically, the addition of electron-donating groups (EDGs) can convert the nitrile imine into a pseudo “type I” dipole. This occurs through the raising of the LUMOdipole energy to the point where LUMOdipole/HOMOdipolarophile interactions are no longer significant. Consequently, such modification increases the reactivity of the nitrile imines with electron-deficient dipolarophiles while reducing their reactivity with electron-rich dipolarophiles. This strategy has been shown to require substitution on the N-terminus of the nitrile imine C–N–N fragment, as substitution of the C-terminus is less effective in raising the orbital energy.

1,3-Dipolar cycloaddition reactions of nitrile imines to thione-containing dipolarophiles produce heterocycles containing a 1,3,4-thiadiazole/thiadiazoline ring, which have interesting pharmacological properties. ,

In view of the reactivity, the C=S bond readily participates in cycloaddition reactions, usually significantly more easily than other C=X bonds. , This is primarily because its LUMO has shown a lower energy level compared to the LUMOs of C=C, C=N, and C=O bonds. Moreover, the cycloaddition of nitrile imines to substrates containing C=S, C=C, C=O, or C=N groups predominantly occurs through the sulfur–carbon bond in most cases. − Thus, thiocarbonyl compounds are sometimes referred to as “super dipolarophiles.”

In this study, we investigated the cycloaddition reactions of nitrile imines with 5-methylidenehydantoin and 5-methylidene-2-thiohydantoin derivatives. The 1,3-dipolar cycloaddition of nitrile imines to arylidenethiohydantoins, which are structurally similar to methylidenethiohydantoins, has also been poorly studied. Thus, in Elwan and Abdelhadi’s work, the [3 + 2]-cycloaddition of nitrile imines to 1-phenyl-5-phenylmethylene-2-thioxothiazoliden-4-one proceeded C=S selective in the presence of C=C and C=O double bonds (Scheme a).

1. Site Selectivity and Regiochemistry of Nitrile Imines, Generated in Situ from Hydrazonoyl Halides under Basic Conditions, in 1,3-Dipolar Cycloaddition Reactions with Substrates Containing C=C, C=O, and C=S Exocyclic Double Bonds .

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a Works mentioned: (a) Elwan et al., 1995; (b) Hassaneen et al., 1995; (c) Yavari et al., 2021; (d) our previous work, 2023.

Very few examples of carbon–carbon double bonds outcompeting carbon–sulfur double bonds in the NI cycloaddition exist in the literature. , Studies on the cycloaddition reactions of a thioketene species demonstrate complete selectivity for the formation of thiadiazoline over pyrazoline. However, Hassaneen et al.’s work showed that the C=S bond in 1,3-diphenyl-5-phenylmethylene-2-thiono-4-imidazolidinone, while being more reactive than the C=O double bond, is less reactive than the enone moiety (Scheme b).

Interestingly, in the work by Yavari et al., the 1,3-dipolar cycloaddition of nitrile imines occurred at both C=C and C=S bonds of arylidenethiohydantoins (Scheme c). However, there are no studies reported that investigate the competition between C=CH2 and C=S groups in reactions with nitrile imines.

In our previous work, it was shown that the cycloaddition of nitrile imines to the 1,1-disubstituted exocyclic carbon–carbon double bond of 5-methylidene hydantoin occurs regioselectively at the C=CH2 bond under mild conditions, leading to spiro-imidazolidinedione-pyrazolines with high yields (Scheme d). In this study, we investigated the influence of electronic effects of substituents in the 1,3-dipole on the chemoselectivity of competing cycloaddition reactions of nitrile imines at the C=C and C=S bonds. We utilized hydantion and thiohydantoin derivatives, specifically 5-methylidene-2-thiohydantoin 1, 1-benzyl-5-methylidene-2-thiohydantoin 4, and 1-benzyl-5-methylidene hydantoin 18, as model substrates. Furthermore, for dipolarophile 18, we evaluated the effect of the electronic effects of substituents in NIs on the cycloaddition reaction efficiency. The observed chemoselectivity for substrate 4 was also analyzed through DFT studies.

Results and Discussion

In the present work, we investigated the patterns of chemoselectivity in the cycloaddition of nitrile imines to dipolarophiles containing 1,1-disubstituted multiple bonds C=C and C=S, where 5-methylidene-2-thiohydantoin 1 was initially selected as the dipolarophile. Nitrile imines are unstable under standard conditions and are typically generated in situ from hydrazonyl halides through treatment with a base, causing deprotonation and subsequent elimination of the halide (Scheme ). Hydrazonoyl chlorides 2a–s, synthesized according to literature methods , (see the Supporting Information, Pages S3–S5), were used as sources of nitrile imines in this study.

We initiated our study by optimizing the cycloaddition reaction conditions involving 5-methylidene-2-thiohydantoin 1 and hydrazonoyl chlorides 2a, c, i, m, and o. Initially, the reaction was performed according to the protocol outlined in our previous work (Entry 1). Hydrazonoyl chloride 2a and dipolarophile 1 were solubilized in acetonitrile (MeCN), and triethylamine was added dropwise under an inert atmosphere at room temperature. This method is indicated in Scheme as the direct addition order (Scheme ; see the Supporting Information for the full Table S1).

2. Optimization of Cycloaddition Reaction Conditions of Hydrazonoyl Chlorides 2 with 5-Methylidene-2-thiohydantoin 1 .

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a Unless otherwise noted, the reaction was carried out at room temperature with 5-methylidene-2-thiohydantoin 1 (0.196 mmol, 40 mg) and the corresponding hydrazonoyl chlorides in 4.0 mL of solvent for 24 h.

b Isolated yield.

c The reaction was carried out at 0 °C.

d The reaction proceeded for 1 h.

e The reaction proceeded for 2 days.

f The reaction proceeded for 5 days.

During a series of experiments (Entries 1–5), we found that varying the solvent, temperature, and reagent ratios did not lead to the formation of cycloaddition products in the case of nitrile imines containing substituents on the aromatic ring at the carbon atom of the C–N–N framework (C-terminus). Specifically, in dichloromethane (DCM), a complex mixture of products was formed, with no target cycloadducts detected. Notably, successful formation of spiroadduct 3a (Entries 6 and 7, with yields of 10 and 25%, respectively) was observed exclusively when hydrazonoyl chloride with an electron-withdrawing substituent on the aromatic ring at the N-terminus was employed. The low yields of cycloaddition products are presumably due to the instability of 5-methylidene-2-thiohydantoin 1 in a basic medium. The addition of a base to the reaction mixture results in the cleavage of the labile NH proton, which subsequently leads to polymerization. We also performed the cycloaddition reaction using a diffusion mixing method; however, this resulted in a lower yield of the spiroadduct (Entry 8).

To suppress side reactions associated with the cleavage of NH proton and to improve the yield of cycloaddition products, we implemented a reverse addition order of the reagents. In this approach, nitrile imines are generated from hydrazonoyl chlorides 2 in the presence of Et3N, followed by the subsequent addition of the dipolarophile 1 (Entries 9–12). This method, along with DCM as a solvent, enabled us to isolate product 3a in 71% yield (Entry 12). The structure of product 3a was confirmed through X-ray spectroscopy (Scheme ). Notably, the reaction was accompanied by isomerization of the carbon–carbon double bond to an endocyclic position, proceeding exclusively through the C=S bond. To the best of our knowledge, there are no prior reports of such transformations involving methylidenethiohydantoins.

3. Reaction Scope .

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a Reaction conditions: 1 (1 equiv, 0.196 mmol, 40 mg), 2 (1.5 equiv, 0.294 mmol), Et3N (2 equiv, 0.392 mmol, 40 mg), 4.0 mL of DCM, Ar, rt, 24 h.

Using optimized conditions, we successfully isolated spiroadducts 3a–c, as shown in Scheme . It is noteworthy that the yield of spirothiadiazolines 3 significantly decreases when moving from EWG-containing nitrile imines (3a and 3b) to those with halogen substituents (3c and 3d). Furthermore, the presence of an electron-donating substituent results in a complex mixture of products, and cycloaddition product 3e was not detected. It is also important to note that in none of the cases were byproducts resulting from nitrile imine dimerization or acylhydrazine formation detected in amounts sufficient for isolation or structural characterization. The position of the substituents within the 1,3-dipole significantly influences the reactivity of nitrile imines in their reaction with 5-methylidene-2-thiohydantoin 1. Specifically, when a nitro group is located in the aromatic ring at the N-terminus, product 3a is formed with a significantly higher yield (71%) compared to that of product 3b (34%), which was obtained using a 1,3-dipole featuring a nitro group in the aromatic fragment at the C-terminus.

Based on the data obtained, we propose the reaction mechanism illustrated in Scheme . In the presence of a base, 5-methylidene-2-thiohydantoin 1 is deprotonated to form intermediate I, which can undergo isomerization of the double bond to an endocyclic position, resulting in the resonance form II. Intermediate II can then be protonated to yield compound III, which readily reacts with an excess of the nitrile imine generated in situ through dehydrohalogenation by the base. This enables the cycloaddition of the nitrile imine to occur via the sulfur–carbon bond, leading to the formation of a 1,3,4-thiadiazoline ring.

4. Proposed Mechanism.

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Additionally, intermediate I can exist as a resonance form IV, which is stabilized by the localization of the negative charge on the sulfur atom. The interaction of intermediate IV with starting compound 1 leads to subsequent polymerization. The introduction of electron-withdrawing substituents into the structure of nitrile imines likely enhances the reactivity of these 1,3-dipoles toward the sulfur–carbon bond in 5-methylidene-2-thiohydantoin 1, especially in relation to intermediate III. Thus, the presence of electron-withdrawing groups increases the rate of the cycloaddition reaction, allowing it to outcompete the rate of the side polymerization process and facilitating the isolation of target compounds with higher yields.

Consequently, the 1,3-dipolar cycloaddition of nitrile imines with 5-methylidene-2-thiohydantoin 1 occurs chemoselectively and regioselectively via the C=S bond. The efficiency of this reaction is influenced by the electronic effects of substituents in the 1,3-dipole, with EWG-containing nitrile imines demonstrating the highest reactivity.

To further investigate the reactivity of nitrile imines with hydantoin derivatives, we chose 1-benzyl-5-methylidene-2-thiohydantoin 4 as the dipolarophile (for synthesis, see the Supporting Information, Pages S6 and S7). This compound contains accessible sites for cycloaddition, including 1,1-disubstituted carbon–carbon and sulfur–carbon bonds, while lacking a labile proton at the nitrogen atom N1. This feature minimizes the risk of side reactions related to isomerization and subsequent polymerization. In line with the characteristic selectivity of nitrile imines for addition through the sulfur–carbon bond, we primarily anticipated the formation of spiro compound 5a.

The optimization of reaction conditions for the [3 + 2]-cycloaddition was first carried out using 1-benzyl-5-methylidene-2-thiohydantoin 4 in conjunction with hydrazonoyl chloride 2a. The in situ generation of the corresponding nitrile imine was facilitated by triethylamine (Scheme ). Unexpectedly, the anticipated product resulting from addition via sulfur–carbon bond 5a was not detected in the reaction mixture, irrespective of the ratios of hydrazonoyl chloride 2a, dipolarophile 4, and triethylamine. This observed chemoselectivity is unusual for nitrile imine cycloadditions; existing literature suggests that when a dipolarophile contains both C=C and C=S bonds, reactions typically proceed through the sulfur–carbon bond. ,−

5. Optimization of Cycloaddition Reaction Conditions of Hydrazonoyl Chloride 2a with 1-Benzyl-5-methylidene-2-thiohydantoin 4 .

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a Unless otherwise noted, the reaction was carried out at room temperature with 1-benzyl-5-methylidene-2-thiohydantoin 4 (0.17 mmol, 50 mg) and hydrazonoyl chloride 2a in 4.0 mL of solvent.

b Isolated yield.

c The reaction was carried out using the diffusion mixing method.

The highest yields of compound 5b were obtained by performing the reaction in dichloromethane (DCM) with 1.1 equiv of hydrazonoyl chloride 2a, one equivalent of 1-benzyl-5-methylidene-2-thiohydantoin 4, and 2.2 equiv of triethylamine (Entry 4). Increasing the concentration of nitrile imine in the reaction mixture resulted in a greater proportion of the product formed with the sequential cycloaddition of two molecules of dipole 5c (Entry 5). Notably, employing three equivalents of hydrazonoyl chloride 2a alongside six equivalents of the base (Entry 6) yielded spiro compound 5c with a remarkable yield of 94%.

The chemoselectivity and regioselectivity of the nitrile imine cycloaddition through the C=C bond were clearly established based on the X-ray analysis of product 5b. Notably, the addition of a second nitrile imine molecule to form product 5c occurs with both regioselectivity and diastereoselectivity. The formation of a single diastereomer as the product is supported by 1H and 13C NMR spectroscopy data from the reaction mixtures and the X-ray of the final product.

Under optimized conditions, we successfully synthesized a series of compounds 5–17 (Scheme A: reagent ratio 4/2/Et3N = 1:1.1:2.2). We varied the substituents in the nitrile imine structure to investigate how their electronic effects influence the chemoselectivity of the 1,3-dipolar cycloaddition. We hypothesized that incorporating electron-withdrawing groups (EWGs) into the nitrile imine structure would modify the reaction’s chemoselectivity by reducing the energy of the dipole’s frontier orbitals. Notably, for 5-methylidene-2-thiohydantoin 1, dipoles containing EWGs exhibited the highest reactivity toward the C=S bond.

6. Influence of the Electronic Effects of Substituents in the Nitrile Imine on the Chemoselectivity of the 1,3-Dipolar Cycloaddition Reaction with 1-Benzyl-5-methylidene-2-thiohydantoin 4 .

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a Unless otherwise noted, in case (A), the reaction was carried out at room temperature with 1-benzyl-5-methylidene-2-thiohydantoin 4 (0.17 mmol, 50 mg, 1 equiv), hydrazonoyl chlorides 2 (0.187 mmol, 1.1 equiv), and Et3N (0.374 mmol, 2.2 equiv) in 4 mL of DCM for 24 h. In case (B), the reaction was carried out at room temperature with 1-benzyl-5-methylidene-2-thiohydantoin 4 (0.17 mmol, 50 mg, 1 equiv), hydrazonoyl chlorides 2 (0.340 mmol, 2 equiv), and Et3N (0.679 mmol, 4 equiv) in 4 mL of DCM for 48 h.

To illustrate the relationship between changes in chemoselectivity and the electron-withdrawing properties of substituents in nitrile imines, we presented our findings in a diagram (Scheme ). In this diagram, the columns represent the yields of the corresponding cycloaddition products: a (C=S), b (C=C), and c (both C=S and C=C), arranged so that the electron-withdrawing properties of the substituents increase along the horizontal axis (Scheme ).

The data obtained indicate that the use of nitrile imines with electron-donor substituents (Entry 1), halogens (Entries 3–5), or no substituents in the benzene ring (Entry 2) resulted in a chemoselective reaction via the C=C bond, yielding spiropyrazoline derivatives 5–9b as the primary products. When an electron-withdrawing substituent was introduced into the aromatic fragment at the C-terminus (Entry 6), a mixture of products was observed, with 10a yielding 10% and 10b yielding 70%. For nitrile imines containing a nitro group in the aromatic ring at the N-terminus (Entries 7 and 8), the product formed via the C=S bond became predominant, with yields of 11a and 12a at 36 and 51%, respectively.

In experiments utilizing a 2-fold excess of hydrazonoyl chloride 2 (Scheme B: reagent ratio 4/2/Et3N = 1:2:4), we anticipated that product c resulting from the sequential addition of two nitrile imine molecules via both C=C and C=S bonds would dominate, irrespective of the electronic effects of the substituents. However, for nitrile imines containing electron-donor substituents (Entries 9 and 10), products formed via the C=C bond (13b and 14b) were predominant. Nitrile imines lacking substituents in their aromatic fragments (Entry 11) and those containing halogens (Entries 12–14) predictably favored products of type c. Notably, a significant increase in yield for product 11c (70%) was observed with nitrile imines containing an electron-withdrawing substituent in the aromatic ring at the N-terminus (Entry 16).

Thus, in the case of nitrile imines containing EDGs or halogens, chemoselectivity was observed with respect to the C=C bond, resulting in the formation of spirocompounds of type b upon the addition of the first nitrile imine molecule. This spirocompound can subsequently undergo [3 + 2]-cycloaddition with a second nitrile imine molecule via the available C=S bond, which is less reactive toward more nucleophilic dipoles, leading to a decrease in the yield of product c. The findings from the second series of experiments (B) corroborate the trends identified in the first series (A).

Conversely, nitrile imines with EWGs in the first series of experiments (A) displayed increased reactivity toward the C=S bond while also participating in reactions through the C=C bond. Therefore, during the sequential cycloaddition of two nitrile imine molecules containing EWGs, both spiroadducts formed in the initial stages, a and b, effectively engage in cycloaddition reactions with a second 1,3-dipole.

The structures of synthesized compounds 5–17 were confirmed using NMR and high-resolution mass spectrometry techniques. X-ray crystallography data were also obtained for compounds 7b and 11a (see the Supporting Information, Pages S42–S52). Notably, for compounds of type c, the 1H NMR spectra exhibited a single set of signals, indicating the diastereoselectivity in the reaction during the sequential cycloaddition of two 1,3-dipole molecules.

To demonstrate the practical utility of the proposed method, gram-scale experiments were conducted under optimized conditions (Scheme C). Notably, the target products 5b (1.63 g, 85%), 5c (0.25 g, 9%), 10a (0.05 g, 5%), 10b (2.04 g, 71%), and 10c (0.58 g, 14%) were obtained without significant loss in yields (for details, see the Supporting Information, Pages S16 and S22).

We have also tested the cytotoxicity of some synthesized spiro-hydantoins (compounds 3a, 12a, 12b, and 19g). However, all these compounds were found to have poor cytotoxicity on colorectal carcinoma HCT116 cell line (>100 μM, see the Supporting Information, Page S55).

Subsequently, 1-benzyl-5-methylidenehydantoin 18 was introduced as the dipolarophile in reactions with nitrile imines, where only the carbon–carbon double bond is available for cycloaddition (Scheme ).

7. Reaction Scope .

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a The reaction proceeded for 24 h, then an additional amount of hydrazonoyl chloride (1.1 equiv) and Et3N (2.2 equiv) was added, and the reaction was allowed to stir for another 24 h.

b Reaction conditions: 1-benzyl-5-methylidenehydantoin 18 (0.18 mmol, 50 mg, 1 equiv), hydrazonoyl chloride 2 (0.198 mmol, 1.1 equiv), Et3N (0.055 mL, 0.395 mmol, 2.2 equiv), DCM, rt, 24 h.

Unlike our previous study, substrate 18 features a benzyl substituent at the N1 atom, leading us to hypothesize that rearrangements resulting in the formation of pyrazole products would not occur in this case. Additionally, we aimed to investigate the influence of the substituent at the N1 position on the reactivity of the hydantoin derivatives. The reaction was conducted under conditions previously demonstrated to be most effective for 1-benzyl-5-methylidene-2-thiohydantoin 4. In this series of experiments, we also varied the substituents in the nitrile imine structure to assess their effect on dipole reactivity. The results of these experiments are presented in Scheme .

In the case of 1-benzyl-5-methylidenehydantoin 18, a dependence of the yields of products from the 1,3-dipolar cycloaddition reaction on the electronic effects of substituents in the nitrile imine molecules was observed. Specifically, the use of nitrile imines containing halogens or electron-donor methoxy groups resulted in high yields of cycloaddition products 19a–d. However, when employing EWG-containing nitrile imines, the yields of spiroadducts 19f–h began to decrease significantly. For instance, the introduction of a 1,3-dipole with a nitro group at the C-terminus of the nitrile imine yielded product 19f at 76%. In contrast, when the electron-withdrawing substituent was positioned at the N-terminus, the yield of compound 19g dropped to 50%. This observed relationship between product yields and the position of the substituent confirms that the substituents at the N-terminus exert a greater influence on the nitrile imine properties. The lowest yield in the [3 + 2]-cycloaddition reaction with 1-benzyl-5-methylidenehydantoin 18 was recorded when using a nitrile imine substituted with a strong electron-withdrawing CF3-group at the C-terminus (19h, 28%). Despite using additional amounts of hydrazonoyl chloride 2s and base during the experiment, full conversion of 1-benzyl-5-methylidenehydantoin 18 was not achieved. Moreover, no byproducts related to nitrile imine dimerization were detected in the reaction mixture, and the separation of the crude mixture allowed for the recovery of the unreacted hydrazonoyl chloride 2s.

The data obtained confirm that the substituent in the aromatic ring at the N-terminus significantly influences the reactivity of 1,3-dipoles of this type. Additionally, it was shown that the reactivity of nitrile imines toward the exocyclic carbon–carbon bond at position 5 of 1-benzyl-5-methylidenehydantoin 18 diminishes with the introduction of electron-withdrawing substituents into the nitrile imine structure.

Theoretical Calculations

To rationalize the observed reactivity of hydantoin H toward nitrile imines N H (Ar2=Ph) and N N (Ar2=Ph­(p-NO2)), we performed DFT studies on the mechanism of the reaction (Figure ; for details, see the Supporting Information, Pages S53 and S54). The reaction of nitrile imines with thiohydantoin 4 is highly exothermic. The Gibbs free energy values for the addition to the C=S bond, the addition to the vinylidene C=C bond, and the sequential addition of two nitrile imine molecules are approximately −35, −60, and −90 kcal/mol, respectively.

1.

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Calculated potential energy surfaces for the reaction mechanisms of thiohydantoin H and nitrile imine N H (A: Ar2=Ph and B: Ar2=4-NO2-C6H4). Gibbs free energies are in kcal/mol; numbers in brackets are relative energy barriers.

In the case of Ph-substituted N H , the transition state TS-C H corresponding to the addition of the nitrile imine to the vinylidene moiety, leading to a C H product, is 4.6 kcal/mol lower in energy than TS-S H , which leads to a C=S bound product S H . At room temperature, this difference in energy barriers corresponds to a ratio of reaction rates of ∼2000:1 in favor of the formation of the C H . Indeed, in the experiment (Scheme , Entry 2), no C=S bound product 7a is formed. Hydantoin is converted into C=C bound product 7b (91%) and the product of double addition 7c (8%). The formation of 7c is due to a 10% excess of nitrilimine used.

In the case of nitro-substituted nitrile imine N N , the calculated energy barrier for the TS-S N leading to the S N is 0.2 kcal/mol lower than the TS-S N leading to C N . This difference in energy barriers leads to the formation of S N and C N products in a 58:42 ratio. Notably, the energy barrier for the second addition of a nitrile imine to C N (TS-CS N ) is 15.2 kcal/mol, which is lower than the barriers for the addition of the first molecule. Thus, C N can partially convert into the double addition product P N . The experimentally observed (Scheme , Entry 8) ratio of 12a:12b:12c = 51:22:6 corresponds to a ratio of C=S and C=C bound monoaddition products of 65:35, which is close to theoretical estimations.

We attribute the difference in reactivity of nitrile imines toward hydantoin to differences in the energies and shapes of their frontier orbitals (Figure S1). The highest occupied molecular orbital (HOMO) in H is primarily localized on the sulfur and exocyclic vinylidene carbon atoms, while the lowest unoccupied molecular orbital (LUMO) of nitrile imines is primarily localized on the C-terminus in the Ar-C–N–N-Ar moiety. In the case of the less electrophilic nitrile imine N H (LUMO at 0.09 eV), a more efficient overlap between the carbon atoms of the vinylidene moiety in H and the Ar-C–N–N-Ar unit provides better stabilization of the transition state TS-C H , leading to the preferential formation of the C=C bound product C H . The introduction of a nitro group in N N significantly decreases the LUMO energy to −0.63 eV, and, consequently, the more efficient interaction with the more negatively charged sulfur atom leads to the formation of the C=S bound product S N .

Conclusions

In this study, we explored the chemoselectivity patterns in the cycloaddition of nitrile imines to dipolarophiles featuring 1,1-disubstituted multiple bonds, specifically focusing on 5-methylidene-2-thiohydantoins. The optimization of reaction conditions revealed that the order of reagent addition and solvent choice is critical for maximizing product yields in the case of dipolarophile 1. Our findings indicate that the electronic effects of substituents in nitrile imines significantly influence the reactivity and selectivity of these reactions. We demonstrated that the use of electron-withdrawing groups in nitrile imines enhances their reactivity toward the C=S bond in 5-methylidene-2-thiohydantoin (1 and 4), leading to higher yields of spiroadducts. Conversely, the presence of electron-donor groups or halogens resulted in a preference for cycloaddition via the C=C bond, yielding different product distributions. Additionally, we established that substituents at the N-terminus of nitrile imines exert a more substantial influence on the reactivity compared to those at the C-terminus. This was particularly evident when comparing yields from nitrile imines with nitro groups at different positions. Overall, our work provides valuable insights into the factors governing chemoselectivity in nitrile imine cycloadditions and highlights the potential for tailoring substituent effects to optimize reaction conditions for desired products.

Supplementary Material

ao5c07709_si_001.pdf (5.1MB, pdf)
ao5c07709_si_002.zip (3.9MB, zip)
ao5c07709_si_003.xyz (68.4KB, xyz)

Acknowledgments

This work was supported by the Russian Science Foundation (project 24-13-00004 (1,3-dipolar cycloaddition reactions) and project 24-23-00173 (hydrazonoyl chloride synthesis and DFT calculations)). DFT calculations were done by M.S.N. within the State Program of TIPS RAS.

Data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c07709.

  • Detailed experimental procedures and full spectroscopic characterization of all products, including 1H NMR, 13C NMR, 19F-NMR, HRMS, computational details (PDF)

  • X-ray crystallographic analysis of 3a, 5b, 5c, 7b, 12b, 19a, and 19c (ZIP)

  • Optimized geometries (XYZ)

Deposition Numbers 2388420–2388423, 2388425, 2404140, and 2404141 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Center (CCDC) and Fachinfomationszentrum Karlsruhe Access Structures service.

All authors have given approval to the final version of the manuscript.

Any funds used to support the research of the manuscript should be placed here (per journal style).

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao5c07709_si_001.pdf (5.1MB, pdf)
ao5c07709_si_002.zip (3.9MB, zip)
ao5c07709_si_003.xyz (68.4KB, xyz)

Data Availability Statement

Data underlying this study are available in the published article and its Supporting Information.

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