1,2,6-Thiadiazine 1-Oxides: Unsaturated Three-Dimensional S,N-Heterocycles from Sulfonimidamides

: Unprecedented three-dimensional 1,2,6-thiadiazine 1-oxides have been prepared by an aza-Michael - addition/cyclization/condensation reaction sequence starting from sulfonimidamides and propargyl ketones. The products have been further functionalized by standard cross-coupling reactions, selective bromination of the heterocyclic ring and conversion into a β - hydroxy substituted derivative. A representative product was characterized by single crystal X-ray structure analysis. Among sulfur-containing biologically active compounds, sulfonamides have hold a pole position for decades being present in a plethora of medicinal and agricultural relevant molecules. 1,2 In contrast, only marginal attention has been paid to their mono-aza analogues sulfonimidamides. Just recently a rising interest for using sulfonimidamides as bioisosters of sulfonamides in the design of bioactive compounds has been noted, both in academic research and industry. 3,4 One reason

Among sulfur-containing biologically active compounds, sulfonamides have hold a pole position for decades being present in a plethora of medicinal and agricultural relevant molecules. 1,2In contrast, only marginal attention has been paid to their mono-aza analogues sulfonimidamides.Just recently a rising interest for using sulfonimidamides as bioisosters of sulfonamides in the design of bioactive compounds has been noted, both in academic research and industry. 3,4One reason for this growing interest is rooted in their attractive and tunable physico-and biochemical properties, such as high metabolic and chemical stability and adjustable donor-acceptor attributes. 5Moreover, introduction of the second nitrogen substituent offers the opportunity of potential chirality and possible modifications in defined three-dimensional directions.In this context, cyclic sulfonimidamides are particularly interesting, serving as building blocks for feasible threedimensional heterocycles with two endo-cyclic nitrogens included in the heterocycle, or with one endo-and one exocyclic nitrogen substituent.Moreover, the construction of annulated ring systems is possible (Figure 1, top).Surprisingly, so far only a few cyclic sulfonimidamides have been reported. 6For example, researcher at Hoffmann-La Roche investigated six-and seven-membered cyclic or bicyclic sulfonimidamides as BACE1 inhibitors for potential treatment of Alz-heimer´s disease (Figure 1, A). 6g-j BASF Agrochemicals developed cyclic sulfonimidamide derivatives of the marketed insecticide sulfoxaflor with the aim to improve physicochemical properties and reduce toxicity in a series of pesticides (Figure 1, B). 6k,l Further cyclic sulfonimidamides have been reported as bioisosters of carboxylic acids 6c or sultams 6d (Figure 1, C).Recently, our group reported benzoisothiazole derivatives as three-dimensional cyclic sulfonimidamides with an exo-cyclic nitrogen substituent (Figure 1, D). 6e Surprisingly, to the best of our knowledge, no unsaturated cyclic sulfonimidamides have been reported to date.Thus, we felt challenged to contribute in this field by developing a synthetic method for these compounds.In particular, the syntheses of 1,2,6-thiadiazine 1-oxides was envisaged (Figure 1, top right corner).
Inspired by previously reported protocols from Williams and Cram 7 and an improved protocol by our group 8 for an aza-Michael addition/cyclisation/condensation reaction sequence between sulfoximines or sulfondiimides and propargyl ketones, we hypothesized that a complementary methodology could access the desired heterocycles. 9For the optimization studies, 4methylbenzenesulfonimidamide (1a) and 1,3-diphenylprop-2yn-1-one (2a) were chosen as representative test substrates.The first reactions were performed in DMSO at room temperature and at 80 °C for 24 h without adding base.Under these conditions, no product formation was observed (Table 1, entries 1 and 2).Following reported conditions from Williams and Cram for the syntheses of unsaturated cyclic sulfoximines, 7 we tested sodium hydride as base, which furnished the product 3aa in 47% yield (Table 1, entry 3).An increase of the temperature had no influence on the yield (Table 1, entry 4).After testing of different bases (Table 1, entries 5-9), we finally applied our previously reported conditions for the syntheses of unsaturated cyclic sulfoximines and sulfondiimides, 8 with Cs 2 CO 3 as base at 80 °C.Now, product 3aa was isolated in 82% yield (Table 1, entry 10).Pleasingly, elevated temperatures were not necessary for this transformation, and at ambient temperature 3aa was obtained in a yield of 88% (Table 1, entry 11).At this stage, we also tested the reaction in air and with a reduced amount of Cs 2 CO 3 , but in both cases the yield dropped dramatically (Table 1, entries 12 and 13).Diminished yields were also obtained when the amount of propargyl ketone 2a or the amount of the base were increased (Table 1, entries 14 and 15).After having identified Cs 2 CO 3 as the most promising base, different solvents were screened (Table 1, entries 16-19).Taking into account the solubility of Cs 2 CO 3 , we primarily focused on employing polar solvents, 10 but none of the tested solvents gave superior yields compared with DMSO.In conclusion, Cs 2 CO 3 (2.1 equiv) as base in DMSO as solvent at room temperature were identified as optimal reaction condition for this transformation (Table 1, entry 11).
With these reaction conditions in hand, the scope with various sulfonimidamides 1 and propargyl ketones 2 was investigated (Scheme 1).First, the substituents on the propargyl ketone 2 were varied, while 4-methylbenzenesulfonimidamide (1a) was kept as reaction partner (Scheme 1, left).Diarylsubstituted propargyl ketones 2b-l proved to be efficient reaction partners in this transformation, and all heterocyclic products 3ab-al, with exception of the 4-nitrophenyl substituted example 3ak, could be isolated in high to excellent yields.In general, less sterically hindered substrates gave higher yields, as exemplified by ortho-, meta-and para-methylphenyl substituted heterocycles 3ab-ad.With bulky 2,4,6-trimethylsubstituted propargyl ketone 2t as reaction partner the yield of 3at was only 26%.Electronic effects had only a minor influence on the yields.Both substrates with electron-donating groups, such as para-methylphenyl-substituted propargyl ketone 2b, and propargyl ketones with electron-withdrawing groups, such as para-fluorophenyl-substituted 2i and paratrifluoromethylphenyl-substituted 2j gave the corresponding heterocycles 3ab, 3ai, and 3aj in high to excellent yields.Heteroaryl-substituted propargyl ketones 2am and 2an could also be engaged in this reaction, furnishing products 3am and 3an in 86% and 43%, respectively.Exemplified by the parachlorophenyl substituted product 3ag, a successful analytical separation of the enantiomers was carried out on chiral-phase HPLC (see Supporting Information).The reaction protocol was also compatible with aryl-alkyl substituted propargyl ketones.For example, heterocycles 3ao and 3ap were isolated in 65% and 78% yield, respectively.The same effects were observed for the heterocycles 3bp and 3cp, varying additionally on the sulfur-substituent.A representative example for a dialkyl-substituted heterocycle is 3as.Terminal alkyne 2q gave 5-unsubstituted heterocycle 3aq in only 13% yield, and no product was observed with phenylpropargyl aldehyde (2u) as substrate.With the intention to further expand the reaction scope, R 1 on the sulfonimidamide 1 was varied next.In this sense 4-bromobenzenesulfonimidamide (1b) and methanesulfonimidamide (1c) were chosen as further reaction partners with differently substituted propargyl ketones 2. To our delight, all of the tested substrates proved to be efficient reaction partners producing the corresponding heterocycles in high to excellent yields (Scheme 1, right).Finally, the reaction was performed on a 1 mmol scale for substrates 1a and 2a.Here, the heterocycle 3aa was isolated in 78% yield.
Single-crystals of 3ao suitable for X-ray diffraction measurement were obtained by slow evaporation of an ethylacetate solution at room temperature.The molecular structure of the tert-butyl substituted heterocycle 3ao revealed a noncoplanar heterocyclic ring with an out-of-plane tilt of the sulfur atom by 0.54 Å (Figure, and Figure S2).According to the work of Lovering and others, 11 who stated that the three-dimensionality is one of the key success factors in drug design, these new heterocyclic sufonimidamide scaffolds could be also interesting from the medicinal and crop protection chemists' point of view.
Figure 2. The ORTEP plot of the molecular structure of 3ao with the thermal displacement parameters at 50 % probability level.
To further illustrate the synthetic value of the prepared heterocycles, para-bromophenyl-substituted products 3ba and 3af have been subjected to two standard cross-coupling reactions (Scheme 2, a and b). 12 For the heterocycle with the parabromophenyl moiety on the sulfur substituent, Suzuki−Miyaura cross-coupling with 4-tolylboronic acid, 2 mol% of Pd(PPh 3 ) 4 as catalyst and K 2 CO 3 as base in refluxing aqueous acetonitrile furnished 4a in 82% yield.Applying a Buchwald−Hartwig-type amination on the same heterocycle with morpholine as coupling partner gave product 4b in a yield of 95% (Scheme 2, a).Employing the same conditions for Suzuki−Miyaura and Buchwald−Hartwig-type reactions to heterocycle 3af resulted in two further cross-coupled products 5a and 5b in 95% and 77%, respectively (Scheme 2, b).
A possible derivatization by modifying the substituent on the sulfur atom was demonstrated by deprotonation of the Smethyl group with n-BuLi and subsequent nucleophilic addition to benzophenone, resulting in β-hydroxy-substituted derivative 6 in 80% yield (Scheme 2, c). 13 At this stage, only position 4 in the newly prepared 3,5disubstituted 1,2,6-thiadiazine 1-oxides remained untouched for possible substituents.With the intention to further functionalize this position, the introduction of a bromine substituent was envisaged, providing a good basis for possible subsequent modifications.Heterocycles 3aa and 3ca were therefore treated with an excess of N-bromosuccinimide in THF for 48 h and 53 h at room temperature.Hence, C4-brominated heterocycles 7a and 7c could be isolated in yields of 81% and 75%, respectively (Scheme 2, d).
In summary, unprecedented three-dimensional unsaturated cyclic sulfonimidamides have been prepared in good to excellent yields.The molecular structure of a representative product was confirmed by single-crystal X-ray diffraction.Product functionalizations were demonstrated by standard crosscoupling reactions, bromination of the heterocyclic ring in addition to functionalization of the endo-cyclic sulfur substituent.

Figure 1 .
Figure 1.Structure of sulfonamides, sulfonimidamides, and sulfonimidamide-based heterocycles with relevance in medicinal chemistry and unprecedented unsaturated cyclic sulfonimidamides as approach of this work.

S
Scheme 1. Substrate Scope with Respect to Sulfonimidamides 1 and Propargyl Ketones 2