Intramolecular cyclization of N-cyano sulfoximines by N–CN bond activation

Abstract

Metal-free halogenated anhydrides promote the intramolecular cyclization of N-cyano sulfoximines. Trifluoro- or trichloroacetic anhydride (TFAA or TCAA, respectively) activate the N-cyano groups of N-cyano sulfoximines, leading to the intramolecular cyclization of 2-benzamide-N-cyano sulfoximines 1. This method results in excellent yields of thiadiazinone 1-oxides 2. A full intramolecular cyclization pattern was suggested by (i) labeling experiments with ¹³C, (ii) isolating of N-trifluoroacetyl sulfoximine 1ac, and (iii) confirming the generation of the intermediate 1ad by LC/MS analysis.

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Introduction

N-Cyano sulfoximines (CN group-substituted sulfoximidoyl moieties) are readily accessible^1–6 and remarkably stable.⁷ Consequently, they are widely accepted as key molecules for drug development^8–10 and crop protection (Fig. 1a).^11–13

Fig. 1 (a) Bioactive N-cyano sulfoximes,^8–13 (b) cleavage of the N-cyano group under aqueous acidic conditions,^{1,2,7,14–16} [3 + 2]-cycloadditions of N-cyano sulfoximines,^17–20 and activation of N-cyano group.^21–25

In addition, owing to the existence of a well-designed method for the cleavage of the N–CN bond, N-cyano sulfoximines have been applied as useful intermediates in the synthesis of NH sulfoximines (Fig. 1b).^{1,2,7,14–16}

While transformations of N-cyano sulfoximines, such as [3 + 2]-cycloadditions, occur at both the carbon and nitrogen atoms of the N-cyano group,^17–20 acid-catalyzed hydrolysis methods have been reported for the cleaving of bonds between nitrogen and the cyano groups.^{1,2,7,14–16} For hydrolysis with aqueous acids, the choice of acid influences the hydrolysis of product; thus, N-urea sulfoximines, a synthetic intermediate of NH sulfoximine, can be produced.^15,26 Furthermore, owing to its strong electrophilic properties, trifluoroacetic anhydride (TFAA) tends to react with relatively weak nucleophiles, such as nitrile groups; based on this strategy, interesting transformations have been applied in the synthesis of N-trifluoroacetyl sulfoximines (Fig. 1b).^24,25

As a representative example of cyclic sulfoximines, benzothiadiazine-1-oxide derivatives, which exhibit improved pharmacological properties, showed enhanced water solubility compared to the 4-aminoquinazoline group of the reference compound Prazosin.²⁷ Previously, using the strategy of cleaving the N–CN bonds of N-cyano sulfoximines, we reported the synthesis of thiadiazine 1-oxides via acid-catalyzed intramolecular cyclization (Fig. 2).²⁶

Fig. 2 Our approaches for the synthesis of thiadiazine 1-oxides²⁶ and thiadiazinone 1-oxides.

The highlight of our method is that it is a metal-free, one-pot reaction using an aqueous acid solution. However, despite the impressive progress made in the development of synthetic routes in recent decades, the introduction of a sulfoximinoyl moiety into a heterocyclic ring system remains challenging owing to the requirement for harsh reaction conditions, expensive transition-metal catalysts, and noncommercial amination reagents.^26,28 To establish highly efficient intramolecular cyclization under mild conditions, our study focused on the N–CN bond activation approach (Fig. 2). Specifically, chemical modifications were designed to maintain the carbon atom of the N-cyano groups of N-cyano sulfoximines in the molecular structures of the products.²⁹ Because of the presence of a lone pair of electrons on the nitrogen atom, the cyano group acts as a Brønsted and Lewis base.^30–34

Results and discussion

We examined metal-free nitrile activation using various anhydrides as the electrophilic reagents. Reacting N-cyano sulfoximine 1a with trichloroacetic anhydride (TCAA) and trifluoroacetic anhydride (TFAA)^24,25 in CH₂Cl₂ for 16 h at room temperature afforded the desired thiadiazinone 1-oxide 2a in yield of 26% and 45%, respectively (entry 1, Table 1). Interestingly, compared to the trichloromethyl (–CCl₃) group, the trifluoromethyl (–CF₃) group showed an enhanced yield owing to its strong electron-withdrawing properties.^35–37 We then screened the amount of anhydrides; the best result (89% yield) was obtained when 6 equiv. of TFAA was added (entry 3, Table 1). The use of other anhydrides, such as acetic, benzoic, and Boc anhydrides, was unsuccessful. Similarly, the use of trifluoromethanesulfonic anhydride (Tf₂O)³⁸ or methanesulfonic anhydride (Ms₂O) as the electrophilic reagent did not afford the desired 2a. Thus, the influence of the choice of electrophilic reagent on this reaction was demonstrated. It is reasonable to assume that the relationship between electrophiles and nucleophiles, such as halogenated anhydride and nitrile, is crucial for obtaining the desired product.

Table 1 Screening of amount of halogenated anhydrides

Entry	Equivalents of halogenated anhydrides	Yield^a (2a, %)
		TFAA	TCAA
a After column chromatography.
1	1	45	26
2	3	74	52
3	6	89	80

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The scope of the reaction was examined under optimized reaction conditions (Scheme 1). For S-methyl and S-phenyl sulfoximines, the desired benzothiadiazinone 1-oxides 2a and 2b were obtained in excellent yields (89% and 78%, respectively). For both heterocycle-substituted N-cyano sulfoximines 1c and 1d, the cyclized products 2c and 2d were obtained in excellent yields (62% and 88%). The electron-donating methoxy group in the N-benzamide position also provided an excellent yield, affording 2e in 66% yield.

Scheme 1 Scope of One-pot synthesis of benzothiadiazinone 1-oxides 2.

We report the X-ray crystal structure of thiadiazinone 1-oxide 2b′, as shown in Fig. 3.^39,40

Fig. 3 X-ray crystal structures of 2b′.^39,40

We considered a mechanism involving N–CN activation, Mumm rearrangement involving O-to-N acyl group migration,^41,42 and intramolecular nucleophilic addition. It is reasonable to propose the formation of intermediate 1aa by TFAA-promoted N-cyano group activation. The hypothesis involving O-to-N acyl group migration is attractive because the carbonyl group is a typical site for intramolecular nucleophilic addition.⁴³ This hypothesis was successfully confirmed by the generation of the intermediate 1ad (Scheme 2, supported by LC/MS analysis experiments).⁴⁴ The results of our study on N-acylated sulfoximine 1ac, which was unreactive, isolable, and very stable, clearly support the proposed mechanism of intramolecular cyclization.⁴⁵

Scheme 2 Proposed mechanism.^41–45

The kinetics of nitrile activation using halogenated anhydrides were monitored using time-resolved NMR spectroscopy. The spectra, recorded during the reaction of 1a with TFAA for 1 h, is illustrated in ESI.† By plotting the integral value of the S-methyl peak of the desired product 2a (3.57 ppm, when integral value of the TMS peak is 1), it can be observed that the concentration of 2a rapidly increased with time when TFAA was used, whereas it remained almost unchanged when TCAA was used (Fig. 3). This experiment proves that the strongly electrophilic TFAA readily reacts with weakly nucleophilic cyano groups (Fig. 4).

Fig. 4 ¹H NMR study of the metal-free nitrile activation using halogenated anhydrides.

To demonstrate that the carbon atom in the resulting molecular structure was derived from the N-cyano group, N-cyano sulfoximine [¹³C]1a was prepared using a¹³C-labeled cyanamide reagent. The reaction of N-cyano sulfoximine [¹³C]1a with TFAA (6 equiv.) in CH₂Cl₂ for 16 h at room temperature readily afforded the desired thiadiazinone 1-oxide [¹³C]2a (entry 1, Table 2). In the case of low temperatures (−10 °C), however, N-trifluoroacetyl sulfxomine 1ac was obtained (entry 2, Table 2). Regarding the mechanism (Scheme 2), compound 1ac was formed by the N-acylation of sulfoximine with TFAA. Importantly, this hypothesis was supported by the experimental results.

Table 2 Mechanistic experiments

Entry	TFAA (eq.)	Reaction conditions	Yield^a (%)
			[^13C]2a	1ac	[^13C]1a
a After column chromatography.b Not obtained.
1	6	RT, 40 min	83	—^b	—^b
2	6	−10 °C, 40 min	21	40	34

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Conclusions

In summary, we have developed a method for the anhydride-promoted intramolecular cyclization of N-cyano sulfoximines. Transition metal catalysts or harsh reaction conditions were not required. We believe that we have identified a clear mechanistic pathway for the activation of the N-cyano groups of N-cyano sulfoximines via the addition of commercially available halogenated anhydrides. We demonstrated the intramolecular cyclization of N-cyano sulfoximines to prepare an important class of sulfoximidoyl heterocycles, thiadiazinone 1-oxides 2, in excellent yields. It is predicted by the KRICT AI platform that thiadiazinone 1-oxides 2 will exhibit excellent drug-like properties with low toxicities (in detail, please see the ESI†).^46–52 Current efforts by our group are directed toward the further application of these attractive molecules for drug discovery.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was supported by the Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry and Energy, and Ministry of Health and Welfare (HN21C1078, Republic of Korea) and by KRICT (KK2331-30 and SI2231-30).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2271515. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ra04208a

‡ These authors contributed equally to this work.

§ Current address: New Drug Development Center, Daegu-Gyengbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea.

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