1,2-Oxa/thia-3-azoles

0 Comprehensive Heterocyclic Chemistry IV Article Title 6.01 1,2-Oxa/thia-3-azoles (included in Volume 6, Other Five-membered Rings with Three or more Heteroatoms, and their Fused Carbocyclic Derivatives) Author and Co-author Contact Information Gonzalo Jiménez-Osés [corresponding author] aCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. blkerbasque, Basque Foundation for Science, Plaza Euskadi 5, 48009 Bilbao, Spain Email: [email protected] +34 946 572 537 Claudio D. Navo Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. Email: [email protected] Francesca Peccati Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. Email: [email protected] Nuria Mazo Arribas 3P Biopharmaceuticals, Polígono Mocholí, C/ Mocholí 2, 31110 Noáin, Navarra, Spain. Email: nmaz[email protected]om Reyes Núñez-Franco Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. Email: [email protected] +34 946 572 538 Abstract In this Chapter, the chemistry of 1,2,3-dithiazoles and 1,2,3-oxathiazoles is covered from 2009 to 2018 inclusive. The 1,2,3-dithiazoles studied are: 1,2,3-dithiazolium cations, 1,2,3-dithiazolyl radicals, 1,2,3-dithiazole-5-ones and related thiones, imines and ylidene compounds, their 5,5disubstituted derivatives, and their 2-oxides. 1,2,3-Oxathiazoles have been investigated in the form of their S-oxides and are also referred to as cyclic sulfamidites, sulfonimidates, sulfimidates and sulfamidates. Keywords 1,2,3-dithiazoles; 1,2,3-dithiazolium cations; 1,2,3-dithiazolyl radicals; bis-dithiazolyl radicals; 1,2,3-dithiazole-5-ones; 1,2,3-dithiazole-5-thiones; 1,2,3-dithiazole-5-imines; 1,2,3oxathiazoles; sulfamidites; sulfonimidates; sulfimidates; sulfamidates; β-aminoalcohols, amino acids. Nomenclature All acronyms and abbreviations are defined throughout the manuscript. 1 6.01 1,2-Oxa/thia-3-azoles 6.01.1 Introduction 2 6.01.2 Theoretical Methods 2 6.01.3 Experimental Structural Methods 4 6.01.3.1 X-Ray Diffraction 4 6.01.3.2 1H NMR Spectroscopy 6 6.01.3.3 13C NMR Spectroscopy 7 6.01.3.4 UV Spectroscopy 8 6.01.3.5 ESR Spectroscopy 9 6.01.3.6 Cyclic Voltammetry 9 6.01.3.7 IR Spectroscopy 10 6.01.3.8 Mass Spectrometry 10 6.01.4 Thermodynamic Aspects 11 6.01.5 Reactivity of Fully Conjugated Rings 11 6.01.5.1 Unimolecular Thermal Reactions 11 6.01.5.2 Electrophilic Attack at Ring Atoms 12 6.01.5.3 Nucleophilic Attack at Ring Sulfur 12 6.01.5.4 Nucleophilic Attack at Ring Carbon 14 6.01.5 Reactions Involving Radicals, Electron-Deficient Species, Reducing Agents, and at Surfaces 19 6.01.6 Reactivity of Nonconjugated Rings 20 6.01.6.1 Reactions of Hydrogenated Derivatives of 1,2,3-Oxathiazole S-Oxides 20 6.01.7 Reactivity of Substituents Attached to Ring Carbon Atoms 22 6.01.8 Reactivity of Substituents Attached to Ring Heteroatoms 24 6.01.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component 25 6.01.9.1 Formation of One Bond Adjacent to a Heteroatom 25 6.01.9.2 Formation of Two Bonds: Four-Atom Fragment and Sulfur 26 6.01.9.3 Formation of Two Bonds: [3+2] Atom Fragment by Cycloaddition 27 6.01.9.4 Formation of Two Bonds: [3+2] Atom Fragment by Other Processes 28 6.01.10 Ring Syntheses by Transformation of Another Ring 30 6.01.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available 31 6.01.12 Important Compounds and Application 31 6.01.13 Further Developments 33 References 33 2 6.01.1 Introduction In this Chapter, the chemistry of 1,2,3-dithiazoles and 1,2,3-oxathiazoles is covered from 2009 to 2018 inclusive. 1,2,5-Oxathiazoles have not been investigated during this period. The chemistry of 4-chloro-1,2,3-dithiazolo-5-imines, -5-ones, -5-thiones, and -5-ylidenes that can readily obtained from Appel salt (4,5-dichloro-1,2,3-dithiazolium chloride) has been greatly expanded with many contributions from the Koutentis and Rakitin groups. The structure and electronic properties of bis-dithiazolyl radicals have been extensively investigated by the combination of many experimental and theoretical techniques. The reactions of cyclic sulfimidates and sulfamidates have been profusely investigated, achieving a dominant position in the preparation of αand β-amino acids, amino alcohols, amines and fused bicycles with high control of chemo-, regioand diastereoselectivity. The 1,2,3-dithiazoles studied are given in Figure 1: 1,2,3-dithiazolium cations 1, 1,2,3-dithiazolyl radicals 2, 1,2,3-dithiazole-5-ones 3 and related thiones, imines and ylidene compounds, their 5,5-disubstituted derivatives 4, and their 2-oxides 5 and 6. 1,2,3-Oxathiazoles have been investigated in the form of their S-oxides and are also referred to as cyclic sulfamidites 7, sulfonimidates 8, sulfimidates 9 and sulfamidates 10. Figure 1 6.01.2 Theoretical Methods Koutentis and co-workers used Density Functional Theory (DFT) methods to analyze the effect of substituents on the preferred ground state spin multiplicity of benzoand azino-fused bis(1,2,3-dithiazoles), unraveling the complex interplay between electronwithdrawing/electron-donating groups and aromaticity (Figure 2).1 Figure 2 DFT calculations were used to assess the relative stability of bis-dithiazolyl radicals in the two dimer configurations (Figure 3) as a function of a coordinate q that is zero for the four-center six-electron dimer (collinear S···S-S···S, a closed shell singlet) and higher for the π radical pair (a triplet). Results indicate that while for the collinear architecture the closed shell singlet is preferred, its relative stability with respect to the triplet sharply decreases with q, which explains the origin of the dimer-to-radical interconversion.2 3 Figure 3 The large polarizability of organic materials has drawn a lot of attention for the development of optoelectronic materials.3 Kishida and co-workers analyzed the non-linear optical properties of the organic biradical naphtho[2,1-d:6,5-d′]bis([1,2,3]dithiazole) 13, set apart from the other compounds presented in this section by the presence of a naphthalene moiety (Figure 4).3 Naphtho[2,1-d:6,5-d′]bis([1,2,3]dithiazole) shows non-linear optical properties with a large third-order nonlinear susceptibility. Computational techniques, in particular spin-unrestricted DFT, helped analyzing the relationship between the diradical characters and the longitudinal second hyperpolarizabilities of cyclic thiazyl compounds and polyacenes, providing general principles for the design of materials for optoelectronics.4 In addition to pure dithiazolyl and diselenazolyl structures, another interesting class of material is represented by derived organic polyiodides, which present interesting conductive and optical properties.5 Figure 4 The stabilities of different sulfamidate radicals and radical cations centered on nitrogen atoms were studied using the G3B3 theoretical method in order to predict reaction enthalpies in 1,5hydrogen atom transfer steps. The N-centered radical of 1,2,3-oxathiazolidine 2,2-dioxide 14 was one of the most stable radicals in the study, suggesting that it would have a very narrow window of synthetic applicability (Figure 5).6 Figure 5 The effects of some substituents at the Cand N-termini of cyclic α-methylisoserine sulfamidates 15 on their reactivity was studied both experimentally and computationally (Scheme 1). It was proven that the reactivity at the quaternary center was silenced when the sulfonamide was unprotected due to accumulation of negative charge at the NSO3 moiety in the transition state. Conversely, acyl groups stabilize such negative charge, thus lowering the activation barrier and triggering the ring-opening. On the other hand, substituents at the C-terminus allow fine-tuning chemoselectivity: SN2 is highly favored with ester groups, and a competition between substitution (leading to pyridinium derivative 16) and elimination (leading to acrylate 17) is observed with amides.7 4 Scheme 1 6.01.3 Experimental Structural Methods In the last years, multidisciplinary studies combining a variety of experimental (and theoretical) techniques have been conducted to elucidate the structural, electronic and magnetic properties of 1,2,3-dithiazolyl and bis-dithiazolyl radicals. Many of the studies covered in this chapter report both the synthesis and structural analysis of relevant compounds with attractive properties from the synthetic and materials point of view. 6.01.3.1 X-Ray Diffraction Bis-dithiazolyl radicals present interesting charge transfer and magnetic properties, which makes them good candidates for the development of nonmetal-based magnetic materials.8 A deep understanding of the solid-state structure of these compounds is of paramount importance for the rationalization of their magnetic behavior, and consequently for the design of compounds with tailored properties. The interest in bis-dithiazolyl radicals lies in their dimorphic nature: they can crystallize in both an α-phase, characterized by π-stacked radical monomers, and in a β-phase, composed of dimers (Figure 3). These dimers are linked through hypervalent four-center six-electron S···S-S···S bonds.2 The α-phase was shown to behave as a Mott insulator, as expected for this type of compound. More interesting is the conductivity of the β-phase: under pressure (around 1 GPa) a phase transformation takes place from the fourcenter six-electron dimer to a π radical pair, with the subsequent metallization of an otherwise semiconducting material. Semiquinone-bridged bisdithiazolyl radicals also display promising properties for the design of single-component molecular electronic and magnetic materials.9,10 The crystal structure of derivative 18, belonging to space group P212121, is characterized by alternating layers giving rise to an ABABAB organization (Figure 6). Contacts among neighboring columns in the π-stacked structure are comparably weak, which apparently could point at a one-dimensional electronic structure prone to spin instability, as observed for other ABABAB stacked radicals. Interestingly, this is not the case for these systems: magnetic susceptibility measurements show that the crystal has a paramagnetic behavior with strong local ferromagnetic interactions (ferromagnetic-coupled π-stacks). Magnetization vs. field measurements indicate a metamagnetic behavior of this material, and in particular with a spin flop transition.9 Analysis of the structure and conductive properties of related chlorinated compounds highlights the importance of oxygen-to-sulfur interactions in determining the tightness of π-stacking, and thus the materials band gap width.9 Figure 6 5 Oakley and co-workers revealed that at low temperature (<5 K) compound 19 shows metamagnetic behavior11 using a combination of X-ray crystallography (structure determinations at 35 and 100 K), DFT calculations and magnetic susceptibility measurements (Figure 7). This behavior is encoded in the solid-state structure in terms of a slipped π-stacked architecture and is likely dominated by inter-stack sulfur-sulfur contacts. The magnetic behavior of the slipped π-stacked arrangement of bis-dithiazolyl radicals is fine-tuned by substituents, as in the case of bis-dithiazolyls bearing fluorine substituents (R2 = F).12 Fluorine substitution also tunes the solid state structure of the bis-dithiazolyl radical 20, which crystallizes into two different phases: a classic slipped π-stack structure and a phase characterized by cross-braced π-stacked arrays of radical dimers.13 Interestingly, the cross-braced π-stacked arrays show a high resistance to dissociation under pressure, as proven by high-pressure crystallographic measurements. Dimer dissociation to a radical pair induced by visible light (650 nm) was interpreted with the help of DFT and Complete Active Space Self-Consistent Field (CASSCF) calculations, underlining the importance of substituent groups in determining the feasibility of dimer-to-radical interconversion as a function of the symmetry of the electronic states involved.13 Oxobenzene-bridged bis-dithiazolyl radicals represent promising building blocks for organic radical-based conductors.14,15 Variable temperature magnetic susceptibility measurements, conductivity measurements, DFT calculations and X-ray diffraction have been used to unravel the properties of an oxobenzene-bridged bis-dithiazolyl radical conductor (21). This analysis reveals that 21 belongs to the rare class of compounds that adopt a bimodal crystal structure with two completely different radical environments.16 Analysis of the electronic structure of these compounds suggests that conductivity starkly depends on the presence of a low-lying LUMO orbital.14,17 Oakley and co-workers showed that substitution on the bis-dithiazolyl radical can fine-tune the stabilization of this orbital modulating the performance of these materials as charge carriers (22).14 Additionally, they showed how structure and conductivity of the prototypical oxobenzene-bridged 1,2,3-bisdithiazolyl radical of this family are highly pressuredependent; indeed, crystal packing responds to the increasing pressure enhancing coplanarity between consecutive radicals in the solid state, which in turn increases conductivity by favoring the formation of a metallic state.18–20 Further analysis accounting for the effect of substitution on bis-dithiazolyl radicals response to pressure ascribes the ease of metallization to their multiorbital character.21 Figure 7 Underlying the delicate interplay between molecular structure and non-covalent interactions in determining the crystal structure, Preuss and co-workers presented the case of 4-benzoyl-1,2,3dithiazol-5-one (23), an achiral molecule that crystallizes in two different morphologies depending on temperature: a racemic form at lower temperatures and a homochiral one at higher temperatures ((Figure 8).22 The same authors reported the first trinuclear metal complex of thiazyl radical 24. Owing to the large spin density at the coordinating atoms, a strong antiferromagnetic coupling is observed between ligand and metal ions, with a spin state of 13/2 in the ground state ((Figure 8).23 6 (Figure 8 Passing a chloroform solution of iminophosphorane 25 through a silica column yielded, along with the already known [5-6-6-6] tetracyclic compound 26, the [6-10-6] tricyclic compound 27 (Scheme 2). Reaction yields depend on the electron affinity and reduction potential of the 1,3,2,4-benzodithiadiazine, and only PPh3 derivative yields the target product.24 The molecular structures of 1,2,3-benzodithiadiazol-2-yl-iminophosphoranes with various degrees of fluorination were obtained by X-ray diffraction, unveiling a novel iminophosphorane structural type in which benzene rings stack on the heterocycle with a surprisingly short inter-ring distance (less than the sum of the van der Waals radii of two carbon atoms). This distance decreases with the increasing degree of fluorination, and as such can be attributed to an arene-polyfluoroarene π-stacking interaction, rather than to packing effects.24 Scheme 2 6.01.3.2 1H NMR Spectroscopy Besides routine characterization of new compounds, no significant developments have been reported in this area since the publication of CHEC-III (2008).25 6.01.3.3 13C NMR Spectroscopy Besides routine characterization of new compounds, no significant developments have been reported in this area since the publication of CHEC-III (2008).25 6.01.3.4 UV Spectroscopy Besides routine characterization of new compounds, no significant developments have been reported in this area since the publication of CHEC-III (2008).25 6.01.3.5 ESR Spectroscopy Control of photoinduced spin state changes in organic molecular materials have been drawing increasing attention as the basis for magnetic switching; this phenomenon, however, remains difficult to control in the solid state.26 Oakley and co-workers have controlled this behavior in a bis-dithiazolyl radical inducing dimer-to-radical interconversion obtaining a remarkably thermally stable radical form.26 Analysis of these dimorphic materials has benefited from highfield electron paramagnetic resonance spectroscopy.27 Unraveling of the magnetic properties of bis-dithiazolyl radicals by a combination with X-ray diffraction and DFT/wavefunction-methods 7 calculations has repeatedly highlighted the intimate relationship between magnetic behavior and the strength of π-stacked multicenter interactions.28,29 The pursuit of a metallic radical uncovered the crucial role of substituents in determining the three-dimensional structure, and as a consequence, the conductivity of bis-dithiazolyl radical solids.30 Electron paramagnetic resonance (EPR) or electron spin resonance (ESR) spectroscopy techniques, often in combination with DFT calculations, have provided invaluable insight into the nature of dithiazolyl and diselenazolyl radicals, both in frozen solutions and solid state.8,31,32 For instance, Oakley and co-workers have reported a rare example of an organic kagome basket structure for the radical ion salt of the quinoidal bis-thiazole 28 (Figure 9).33 Figure 9 6.01.3.6 Cyclic Voltammetry No significant developments have been reported in this area since the publication of CHECIII(2008).25 6.01.3.7 IR Spectroscopy Besides routine characterization of new compounds, no significant developments have been reported in this area since the publication of CHEC-III(2008).25 6.01.3.8 Mass Spectrometry Besides routine characterization of new compounds, no significant developments have been reported in this area since the publication of CHEC-III(2008).25 6.01.4 Thermodynamic Aspects Relevant aspects about the structure and stability of stable radicals have been covered in the Xray diffraction Section. No other significant developments have been reported in this area since the publication of CHEC-III(2008).25 6.01.5 Reactivity of Fully Conjugated Rings The reactivity of conjugated 1,2,3-dithiazole-type structures has been covered in CHEC-III (2008).25 Thermal rearrangement of 1,2,3-dithiazoles normally occurs with concomitant loss of one or two sulfur atoms. Oxidation of 1,2,3-dithiazoles occurs at the S2 atom. Nucleophilic attack at ring carbon most frequently takes place in Appel salt and its imino derivatives. Most of the new reactions covered in this Section expand the scope of the Appel salt chemistry and its keto, thio, imino and ylidene derivatives. 6.01.5.1 Unimolecular Thermal Reactions The synthesis of dicyano-1,3,4-thiadiazole (30) from the reaction of 1,2-bis-(4-chloro-5H-1,2,3dithiazol-5-ylidene)hydrazine (29) with benzyltriethylammonium iodide has been reported (Scheme 3).34 Amide 31 was also obtained as a by-product. 8 Scheme 3 Fused oxazoles 35 can be prepared by thermolysis of the corresponding 2-hydroxy-(4-chloro5H-1,2,3-dithiazol-5-ylideneamino)arenes 34, which can be generated from condensation of Appel salt 32 with ortho-aminophenols 33.35 Treating these same intermediates with base results in the selective formation of oxazine-fused dithiazoles 36 (Scheme 4). Scheme 4 Different authors have suggested a route to the synthesis of 1,3-azin-4-one systems 39 and 40, which are relevant for the synthesis of several compounds such as thienopyridines.36,37 1,3-Azin4-one systems are obtained through 2-(1,2,3-dithiazol-5-ylidene)aminothiophene intermediates 38 obtained from the reaction of Appel salt 32 and different aminothiophenes 37 (Scheme 5). Scheme 5 Similarly, the reaction of 1H‑pyrazol-5-amines 41 with Appel salt 32 yields pyrazolo[3,4‑c]isothiazoles 42 and pyrazolo[3,4‑d]thiazoles 44 (Scheme 6).38 With N-1 methylated pyrazoles, chemoselectivity can be modified by adjusting the pH of the reaction medium: acidic conditions favor the formation of dithiazolylidenes 43, while basic conditions favor the formation of pyrazolo[3,4-c]isothiazoles 42. Thermolysis of N-(4-chloro-5H-1,2,3dithiazol-5-ylidene)-1H-pyrazol-5-amines 43 gives 1H-pyrazolo[3,4-d]thiazole-5-carbonitriles 44. Alternatively, treatment of compounds 43 with secondary amines gives 5H-pyrazolo[3,4e][1,2,4]dithiazine-3-carbonitriles 45 in good yields (Scheme 6).39 15 It was also shown that Appel salt 32 can react with dimethylsulfonium dicyanomethylide to yield, under optimized conditions, dithiazolylidene 112 in 72% yield together with small amounts of dithiazol-5-thione 105, 4-chloro-5H-1,2,3-dithiazol-5-one (106) and methylsulfide 113 as a mixture of E/Z isomers (Scheme 20).54 Scheme 20 5-(4-Chloro-1,2,3-dithiazolylidene)malononitrile (112) can be likewise obtained by reacting 4chloro-5H-1,2,3-dithiazole-5-thione (105) with dimethylsulfonium dicyanomethylide in refluxing acetonitrile (Scheme 21).54 Scheme 21 Similarly, Appel salt 32 reacts with dimethylsulfoxide (DMSO) and other sulfoxides 114 to yield 4-chloro-1,2,3-dithiazol-5H-one (106) (Scheme 22).55 Scheme 22 Reaction of Appel salt 32 in wet solvents (CH2Cl2, THF and MeCN) gives, dithiazole-5-thione 105, dithiazol-5-one 106 and thiazol-5-one 115 (Scheme 23).56 Scheme 23 6.01.5.5 Reactions Involving Radicals, Electron-Deficient Species, Reducing Agents, and at Surfaces The (6H-1,2,3-benzodithiazol-6-ylidene)malononitrilidyl radical anion salts 117 and 118, obtained by reduction of 116 with tetrakis(dimethylamino)ethylene were characterized through electron paramagnetic resonance (EPR), UV-Vis spectroscopy and DFT calculations.57 EPR confirms the paramagnetic nature of the radical anion salt 117, both in solid state and in acetonitrile solution, while UV-Vis and DFT calculations concur in attributing to the radical anion in solution an absorption band at 663 nm. Conversely, reduction with bis(toluene)chromium(0) 16 afforded a salt, 118, whose magnetic susceptibility suggests the formation of π-stacked dimers of the radical anion in the solid state (Scheme 24). Scheme 24 Analogously, the hybrid 1,2,5-thiadiazolidyl/1,2,3-dithiazolidyl radical anion 120 was prepared by the electrochemical reduction of the corresponding ylidene obtained from Herz salt 119. 57,58 DFT calculations indicate that the SOMO of this radical anion has a fundamentally antibonding character, and that the net negative charge and spin density are delocalized over the aromatic body of the molecule,58 as observed for other 1,2,3-benzodithiadiazol-based radicals (Scheme 25).59 Scheme 25 The use of neutral radicals such as bis-dithiazolyl radicals as building units for conducting and magnetic materials requires a deep understanding of the relationship between their molecular and solid-state properties (see also Theoretical Methods Section). Radicals naturally tend to dimerize, either through σ or multicenter π-π bonds, and this tendency must be controlled in materials design as spin pairing destroys charge carriers and opens the materials band gaps.2 1,2,3-Dithiazoles have been drawing increasing attention in the field of materials science as precursors for stable radicals. Among them, 5,5'-bis-1,2,3-dithiazoles are a relatively unexplored class of compounds that can serve as templates for preparing conductive charge-transfer salts and diradical species.60 Rakitin and co-workers showed that these compounds can be obtained by reduction of 4-substituted 1,2,3-dithiazolium chlorides 32 and 122 with triphenyl antimony and metals (Ag, Zn, Fe and Cu).60 With Cu powder at room temperature, bis-dithiazoles 121 and 125 can be obtained in moderate to excellent yields, and subsequently thermolyzed to give isothiazolo[5,4-d]isothiazoles 122 and 12661 (Scheme 26). 17 Scheme 26 Rakitin and co-workers analyzed the possibility of synthesizing 1,2,3-benzodithiadiazol-2-yliminophosphoranes 128 by reaction of fluorinated 1,3,2,4-benzodithiadiazines 127 and a series of aromatic phosphines.62 While 1,3,2,4-benzodithiadiazines formally behave as isomeric singlet nitrenes iminating the phosphorous of the phosphine, the reaction mechanism is still unclear. This compound is a precursor of the Herz (5,7-difluoro-1,2,3-benzodithiazolyl) radical 129, which is obtained by thermolysis in decane. Interestingly, this synthetic route gives access to iminophosphoranes that cannot be obtained through Staudinger or Kirsanov reaction (Scheme 27).62 Scheme 27 Oakley and co-workers proposed a series of bis-1,2,3-dithiazolyl radicals.9,10,63 The reaction of diamino-pyridinium triflate 130 in acetonitrile in the presence of S2Cl2 introduces two thiazolylium rings into the scaffold 131; reduction of the triflate salt with tetrakis(dimethylamino)ethylene (TDAE) affords bis-1,2,3-dithiazolyl radical 132, which was isomerized to target radical 133. This radical decomposes upon heating yielding a zwitterionic bis-1,2,3-dithiazolopyridone 134 with loss of an N-methyl group. This process has been shown through EPR analysis to involve radical intermediates (see ESR Spectroscopy Section) (Scheme 28). Scheme 28 A similar synthetic process affords related fluorinated bis-dithiazolyl compound 1352 and cyclohexadienone derivative 189 (Figure 10). 18 Figure 10 Preuss and co-workers proposed a 1,2,3-dithiazolyl-o-naphthoquinone whose oxidized and reduced forms can be isolated.59 The synthesis involves treatment of 4-amino-1,2naphthoquinone (136) with an excess of S2Cl2 to yield the chloride salt of 4,5-dioxo-naphtho[1,2d][1,2,3]dithiazol-2-ium (137), a closed shell cation, through Herz condensation. Reduction yields neutral radical compound 138, and further reduction produces a closed shell anionic compound that is water-stable as a lithium complex 140 (Scheme 29). The crystal structure of the cation salt with a variety of anions reveals essentially constant structural features. The neutral radical crystallizes in a structure whose asymmetric unit is composed of a pancakebonded π-dimer in which bond distances reflect the contribution of both radical resonance structures.59 The anionic form could be crystallized as the hydrated tetramer of the lithium salt, where Li+ is coordinated with a distorted square planar geometry. Carbon-oxygen distances reflect the oxidation state of the anion being significantly larger than the neutral and positively charged counterparts.59 Scheme 29 6.01.6 Reactivity of Nonconjugated Rings The reactivity of cyclic sulfonimidates, sulfamidites and sulfamidates was reviewed in CHEC-III (2008) and is further explored in this Chapter.25 Nucleophilic ring-opening of these compounds has consolidated as an excellent entry to the synthesis of biologically active compounds such as chiral β-amino alcohols and αand β-amino acids. 6.01.6.1 Reactions of Hydrogenated Derivatives of 1,2,3-Oxathiazole S-Oxides Racemic mixture rac-142 was ring-opened by nucleophilic attack of methyllithium to the sulfur atom breaking the endocyclic S–O bond. The corresponding sulfoximine 143 was deprotonated with lithium bis(trimethylsilyl)amide (LiHMDS) and reacted with a second equivalent of rac-142 in a one-pot sequence, to obtain the bis(sulfoximine) rac-144 almost quantitatively and in good diastereomeric ratio (Scheme 30).64 19 Scheme 30 Both diastereoisomers of sulfonimidate 145a,b were separately ring-opened with chloromethyllithium, and the resulting S-(halomethyl)sulfoximines intermediates 146a,b were cyclized to afford cyclic sulfoximines 147a,b, respectively (Scheme 31).65 Scheme 31 On the other hand, the use of lithium aluminum hydride (LAH) leads to 1,2-aminoalcohol derivatives. For instance, treatment of carbohydrate-based sulfimidates 148a,b with LAH afforded methyl α-L-ristosaminide (149a) and methyl α-D-ristosaminide (149b), respectively, in high yields (Scheme 32).66 Scheme 32 Sulfimidates 150 are found to be excellent precursors for the synthesis of a large number of substituted cyclic sulfamidates 151-153 (Scheme 33). The imine group of sulfimidates can be reduced to form the corresponding cyclic sulfamidates 151. Sodium borohydride is one of the most common reagents to selectively reduce the imine group in moderate to high yields.67–70 However, diastereoselectivity highly depends on the substrate, yielding from very low to almost complete stereoselection. Reduction with molecular hydrogen,71–83 or nucleophilic attack of Grignard reagents,84,85 boronic acids86–89 or esters,90,91 among other methods92–95 lead to sulfamidates 151, 152 and 153, respectively. Yields are in general high and stereoselectivity may be achieved depending on the catalyst and ligands used (Scheme 33). 20 Scheme 33 The asymmetric transfer hydrogenation of the imine group of sulfimidates 154 has been widely exploited to obtain enantiomerically enriched cyclic sulfamidates 155. The use of formic acid and triethylamine as the hydrogen source in the presence of a chiral rhodium catalyst (R,R)- or (S,S)-156 is a well-established protocol for the synthesis of chiral cyclic sulfamidates in high yields and enantiomeric excesses (Scheme 34).71–79,81,83 Scheme 34 A polymeric version of chiral ligand (R,R)-156, 157, was also used as a catalyst for asymmetric transfer hydrogenation of cyclic sulfimidate 158 to yield sulfamidate 159 in a high yield and enantiomeric excess (Scheme 35).82 Scheme 35 Asymmetric hydrogenation of sulfimidate 160 using a Pd catalyst and a chiral phosphine ligand, in MeOH, gave cyclic sulfamidate 161 in a high yield and enantiomeric excess (Scheme 36).80 21 Scheme 36 The imine group of sulfimidates 162 can also undergo 1,2-additions leading to gem-disubstituted cyclic sulfamidates 163. A wide variety of Grignard reagents are able to chemoselectively react in moderate to good yields to yield racemic products (Scheme 37).84 Scheme 37 Reaction between racemic cyclic sulfimidate 164 and an excess of methylmagnesium bromide afforded a single racemic diastereomer. Both enantiomers could be separated using a chiral stationary-phase HPLC to obtain the desired enantiomer 165 nearly quantitatively (Scheme 38).85 Scheme 38 The use of chiral organometallic catalysts and boron derivatives allows enantioselective 1,2additions. For instance, a chiral diene-ligated rhodium complex was used to catalyze the addition of potassium allyltrifluoroborate to cyclic sulfimidate 166 affording allylated sulfamidate 167 in a good yield and enantiomeric excess (Scheme 39).93 Scheme 39 The reaction of sulfimidate 168 with arylboronic acid neopentyl glycol esters 169 in the presence of a chiral ferrocenyl tetrafluorobenzobarrelene ligand, allowed the synthesis of gem-diaryl substituted sulfamidates 170 in high yields and enantiomeric purity.90 On the other hand, enantioselective 1,2-additions of aryl pinacolborate esters 171 to cyclic sulfimidates 162 were 22 performed using a chiral bicyclo[3.3.0]octadiene ligand to yield sulfamidates 172 in good yields and enantiomeric excesses (Scheme 40).91 Scheme 40 Enantioselective 1,2-additions of vinyl-, aryl-, and heteroarylboronic acids 173 to cyclic sulfimidates 162 were performed using a rhodium complex with a chiral phosphine86 or a chiral N-sulfinyl amine87,88 as catalysts. The yields of sulfamidates 163 range from moderate to high, as well as the enantiomeric excesses (Scheme 41). Scheme 41 Alternatively, enantioselective arylation of alkyl-substituted cyclic sulfimidates 162 was performed using a variety of arylboronic acids 174 with a palladium-chiral phosphino-oxazoline complex as a catalyst.89 The yields and the enantiomeric excesses of sulfamidates 172 using this procedure are very high (Scheme 42). Scheme 42 23 The imine group of sulfimidates can act as a dipolarophile in 1,3-dipolar cycloadditions. In such a way, azomethine ylides generated in situ from bis((trimethylsilyl)methyl)amines 175 were reacted with sulfimidate 158 giving sulfamidate-fused imidazolidines 176 in low to moderate yields (Scheme 43).95 Scheme 43 Sulfimidate 158 could also undergo a (3+2)-annulation with dimethylbutadiene in the presence of an iridium(I) acetate complex to obtain spirocyclic indene-sulfamidate 177 in high yield and diastereoselectivity (Scheme 44).94 Scheme 44 Treatment of 4-arylsulfimidates 168 with allylic ylides 178 in the presence of a base (potassium t-butoxide) followed by a Pd(0)-catalyzed isomerization allowed the synthesis of a series of cistrisubstituted vinylaziridine-fused sulfamidates 179 in moderate to good yields (Scheme 45).92 Scheme 45 Sulfimidates, as with imines, are in equilibrium with the corresponding cyclic enamines. This process is catalyzed by either an acid or a base and allows the system to react as a nucleophile at C5 (Scheme 46). Scheme 46 Along these lines, arylsulfimidates 162 were condensed with different arylaldehydes 180 using L-proline as an organocatalyst. This procedure gave (Z)-5-alkylidene-substituted sulfimidates 181 in moderate to high yields.67 However, reaction between sulfimidate 158 and α,β-unsaturated aldehydes 182 under the same conditions led to 1,4-addition products 183 and 184 instead of the expected 1,2-adducts (Scheme 47). 24 Scheme 47 A one-pot three-component reaction was developed for the stereoselective synthesis of functionalized fused δ-lactone spiro-sulfimidate derivatives 186a,b. The three-step sequence process involved a 1,4-conjugate addition of sulfimidates 168 to α,β-unsaturated aldehydes 185 followed by a condensation with formaldehyde and a concomitant hemiacetalization, and a final oxidation using pyridinium chlorochromate (PCC).68 The overall yields and diastereoselectivities were generally good (Scheme 48). Scheme 48 A domino reaction of sulfimidates 162 with acetates of nitroolefins and nitrodienes 187 in the presence of DABCO as a base provided 4,6-diarylpicolinates 188 in good to high yields (Scheme 49).96 Scheme 49 In a similar way, domino reaction of sulfimidates 162 with Morita–Baylis–Hillman acetates 189 using DABCO as a base allowed the synthesis of 3-carboxylate/cyano/acetyl-4,6-diarylpyridine derivatives 190 in good to high yields (Scheme 50).97 Scheme 50 31 Scheme 71 1-Bromo-1,1,2,2-tetrafluoroalkane 232 was reacted with a Grignard reagent to afford a stable organomagnesium compound that was subsequently used for regioselectively ring-opening NBoc-1,2,3-oxathiazolidine 2,2-dioxide (233) affording compound 234 in 76% yield (Scheme 72).145 Scheme 72 The enolates of 1,3-dicarbonylcompounds 236 can be readily alkylated by ring-opening of sulfamidates 235.146–149 Likewise, disubstituted acetonitrile derivative 239 was deprotonated and reacted with bicyclic sulfamidate 238 to give compound 240 as a mixture of diastereomers (Scheme 73).111 Scheme 73 Cyanide has also been used to obtain β-amino acids upon ring-opening of sulfamidates and subsequent hydrolysis.113 Along these lines, L-[4-11C]asparagine (242) was synthesized using radiolabeled cyanide and serine-derived sulfamidate 241 (Scheme 74).150 32 Scheme 74 Fluorinating reagents, such as cesium fluoride151,152 or tetrabutylammonium fluoride (TBAF)87,90,109,110 have been used for synthesizing organofluorine compounds 243a by ringopening of sulfamidates 205. This approach has been particularly useful for the synthesis of radiolabeled fluorinated ligands 243b for Positron Emission Tomography (PET) imaging (Scheme 75).102,104,115,118,151–154 Scheme 75 Diarylphosphines,155–158 diarylphosphine oxides,159,160 dialkylphosphites,120 and phosphineborane complexes155,161 have been used as nucleophiles for the ring-opening of sulfamidates 229 to yield 1,2-aminophosphorous compounds 244-247 (Scheme 76). Scheme 76 Carboxylates, such as benzoate derivatives,71,75,76,79,81,83,162–165 acetate,166 or formic acid,74 were extensively used as nucleophiles for ring-opening of sulfamidates 205 to obtain β-aminoalcohol derivatives 248-250 (Scheme 77). 33 Scheme 77 Phenolates react with cyclic sulfamidates 205 yielding β-aryloxyamines 251.73,77,87,90,133,167–174 However, acidic hydrogen atoms at the β-position of the endocyclic oxygen of sulfamidates 252 may be abstracted under these conditions and an elimination reaction takes place to form βamino-acrylate 253 (Scheme 78).169 Scheme 78 Similarly, certain alkoxides were used as O-nucleophiles to synthesize antifungal glucan synthase inhibitors,175 carbasugar analogs,176 or glycosylated amino acids.165,177 Sulfamidates 254, derived from α-methylisoserine, were ring-opened in neutral media by aliphatic alcohols by attack at the quaternary carbon with total inversion of the configuration, thus yielding β2,2-amino acid derivatives 255 (Scheme 79).178 Scheme 79 Remarkably, sulfamidate 256 was ring-opened by the oxygen atom of 2-pyridone in the presence of cesium carbonate as a base to afford tetrahydroisoquinoline derivative 257 (Scheme 80).133 Scheme 80 34 In a similar manner, thiolates, thioates or dithiocarbamate anions were used as S-nucleophiles for the regioselective ring-opening of cyclic sulfamidates 205 in good to excellent yields (Scheme 81). This method allowed the synthesis of 1,4-benzothiazepines,170 unnatural dithiocarbamate amino acids,179 cysteine and cysteamine derivatives,90,112,173,180–182 bis-amino acid lanthionine analogs,105,106,183,184 S-glycoamino acids and peptides,165,185,186 and monosaccharide mimics.187 Scheme 81 The synthesis of β-amino disulfides 261 or β-amino thiols 262 was carried out using tetrathiomolybdate ([BnNEt3]2MoS4) via regioselective ring-opening of cyclic sulfamidates 205 (Scheme 82).101,188 Scheme 82 Reaction of sulfamidate 263 with O-phenyl chlorothionoformate in DMF at 60 °C yielded dihydrothiazole 264 by acylation and ring-opening of the sulfamidate by the sulfur atom of the thionoformate (Scheme 83).89 Scheme 83 β-Amino diselenides 265 were prepared in high yields from cyclic sulfamidates 205 using potassium selenocyanate and tetrathiomolybdate in a sequential, one-pot, multistep reaction.189 On the other hand, reaction of cyclic sulfamidates with diphenyl diselenide in the presence of rongalite (sodium hydroxymethanesulfinate) gave rise to β-amino selenides 266 in good to excellent yields (Scheme 84).180 35 Scheme 84 Sodium azide was commonly used as a reagent to ring-open a wide variety of cyclic sulfamidates in high to excellent yields of β-aminoazides 267.67,68,71,73,75,76,83,112,165,187,190–193 Remarkably, reacting sulfamidates 205 with sodium azide in the presence of terminal alkynes and copper(I) salts resulted in a one-pot click reaction to synthesize triazole derivatives 268.194,195 However, reaction between aziridine-fused sulfamidate 222 with sodium azide in the presence of boron trifluoride diethyl etherate led to the regioand diastereoselective ring-opening of the aziridine moiety toward 269, without affecting the sulfamidate ring (Scheme 85).92 Scheme 85 Primary and secondary amines,84,87,192,196–200 as well as aryland heteroarylamines,116,119,170,171,201– 203 can react with cyclic sulfamidates 205 to afford 1,2-diamine derivatives 270 in good yields (Scheme 86). Natural and unnatural α-amino acids have been used as nucleophiles to synthesize piperazinone derivatives,80 aspergillosamine A and related compounds,204 or α-amino γ-lactams within a peptide sequence.205–207 Ring-opening of cyclic sulfamidates with propargyl, 2hydroxyethyl, and 2-pentynylmethanesulfonamides led to tetrahydropyrazines,208 piperazine derivatives,209 and bicyclic hydantoins,210 respectively. 36 Scheme 86 Certain amides can also react with sulfamidates inducing ring-opening.107,133 For instance, potassium phthalimide was used to synthesize 1,2-diamines 271 after reaction with sulfamidate 205 and deprotection using hydrazine (Scheme 87).211,212 Scheme 87 Aromatic heterocycles, such as pyrazoles,213,214 imidazoles215 or tetrazoles,216 were also used as nucleophiles with several cyclic sulfamidates. Ring-opening of serine-derived sulfamidate 205 with protected histidine allowed the synthesis of bis-amino acid histidine-alanine derivatives 272-275 (Scheme 88).217 Scheme 88 37 Pyrroleand indole-2-carboxylate derivatives were also reported as nucleophiles to prepare pyrrolo-piperazinones 276218,219 and pyrazino-indolones 277220–222 by ring-opening of sulfamidates 205 and subsequent cyclization in the presence of a base (Scheme 89). Scheme 89 Positively charged β2,2-amino acids and hybrid peptides 278 and 279 were synthesized using Nalkylimidazoles, N-alkylindoles or pyridine derivatives as nucleophiles reacting with sulfamidates 205 derived from α-methylisoserine.7,186,223 Ionic liquid crystals were developed from ringopening amino acid based sulfamidates with methylimidazole.224 Several chiral N-heterocyclic carbenes were prepared using N-substituted imidazole derivatives 279 (Scheme 90).225–228 Scheme 90 Enantiomerically pure (β-aminoalkyl)boronic esters 280 were obtained in moderate to good yields by copper-catalyzed borylation of cyclic sulfamidates 205 (Scheme 91).229 Scheme 91 Sulfamidates containing acidic hydrogens at the β-position of the endocyclic oxygen atom, such as amino acid derived sulfamidates, are prone to undergo eliminations in the presence of certain bases. For instance, serine-derived sulfamidite 281 was transformed to dehydroalanine 282 in the presence of triethylamine184 or phenolate rather than undergo ring-opening.169 In a similar manner, α-methylisoserine-derived sulfamidates (283 and 286) reacted with triethylamine185 or pyridine7,186 to obtain β-amino-acrylates 285 and 288 as by-products (Scheme 92). 38 Scheme 92 6.01.7 Reactivity of Substituents Attached to Ring Carbon Atoms Nucleophilic substitution of chlorinated cyclopenta-1,2,3-dithiazoles was profusely covered in CHEC-III (2008)25 and is further expanded in this Chapter. The unexpected formation of 5,5-diethoxy-5H-1,2,3-dithiazoles 289 from 5H-1,2,3-dithiazole-5thiones 66 upon treatment with sodium ethoxide (Scheme 93) was reported.230 Scheme 93 Rakitin and co-workers showed that reaction of 4-substituted 5-ylidene-1,2,3-dithiazoles 290 with two equivalents of n-butylamine yields monoamidines 291 as the addition product of the amine to the nitrile group (Scheme 94).231 Scheme 94 3-Chloro and 3-bromoisothiazole-5-carbonitriles 298 were obtained from (4-chloro-5H-1,2,3dithiazol-5-ylidene)acetonitriles through intermediate 2-chloro 295 and 2bromo(dithiazolylidene)acetonitriles 296.232 Alkylidene dithiazole 294 could be synthetized from 292 by stepwise hydrolysis and decarboxylation or in one step (Scheme 95). 39 Scheme 95 6.01.8 Reactivity of Substituents Attached to Ring Heteroatoms The nitrogen atom of cyclic sulfamidates has a certain nucleophilic character and is able to react with some electrophiles. For instance, reaction of cyclic sulfamides 151 with alkyl halides gives N-alkylation,75,151,152,196 and with acyl chlorides,84,87,89,187,233,234 anhydrides,223 or carbonates68,71,74,77,79,81,83,90,178 in the presence of different bases affords N-acylation (Scheme 96). Scheme 96 Carboxylic acids224 and amino acids185,186 can also be attached to the nitrogen atom of sulfamidates 151 using coupling agents, such as dicyclohexylcarbodiimine (DCC) or 2-(1Hbenzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) in the presence of a base in moderate to high yields (Scheme 97). Low temperatures are commonly used to avoid ring-opening of the sulfamidate by nucleophilic reagents. 40 Scheme 97 1,2,3-Oxathiazolidine 2,2-dioxide 151 was reacted with (diazomethyl)trimethylsilane154 in a mixture of toluene and methanol at room temperature to afford sulfamidate 301. Similarly, 1,2difluoro-4-nitrobenzene was reacted with 151 in acetonitrile under reflux to give the N-aryl sulfamidite 302.235 A tandem ortho C–H olefination/cyclization of cyclic 4-arylsulfamidates with methyl acrylate was developed to form functionalized isoindoline-fused sulfamidates 303 (Scheme 98).73,76 Scheme 98 6.01.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component The synthesis of 1,2,3-dithiazoles was intensively discussed in CHEC-III (2008).25 The use of 4,5dichloro-1,2,3-dithiazolium chloride (Appel salt, 32) has consolidated as the most practical strategy for synthesis of various 1,2,3-dithiazole derivatives, and its applications are further examined in this Chapter. Nitrene insertions of sulfamates into C–H bonds in the presence of rhodium catalysts and hypervalent iodine reagents, has emerged as a very powerful method for the preparation of enantiopure sulfimidates and sulfamidates. 6.01.9.1 Formation of One Bond Adjacent to a Heteroatom Lorpitthaya and co-workers reported the rhodium catalyzed C–H nitrene insertion followed by spontaneous cleavage of a silyl protecting group of a sulfamate 304 derived from D-glucal, which afforded cyclic sulfimidate 305 in a good yield (Scheme 99).236 47 Scheme 113 6.01.10 Ring Syntheses by Transformation of Another Ring Rearrangement of thiazete 1,1-dioxide 358 in the presence of a Lewis acid (ZnCl2) afforded 5H1,2,3-oxathiazole-2-oxide 359 as a mixture of diastereomers (Scheme 114).254 The mechanism for this unprecedented rearrangement was proposed to be similar to the transformation of 3aryl β-sultams into 1,2,3-oxathiazolidines. Scheme 114 48 6.01.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available The widely used protocol to synthesize 1,2,3-dithiazolium salts25 by reacting aromatic amines with S2Cl2 (Herz reaction) has been further explored by many groups and is reviewed in this Chapter. The traditional synthesis of cyclic sulfimidates from 1,2-amino-alcohols and SOCl2 in the presence of organic or inorganic bases has been developed further for the preparation of enantiopure monocyclic and fused sulfimidates. Usually 1,2,3-oxathiazolidine mono-S-oxides are not isolated but readily oxidized to the corresponding sulfamidates by RuO4 generated in situ from RuCl3 and NaIO4. Alternatively, 1,2-amino-alcohols are reacted with SO2Cl2 or 1,1′- sulfonyldiimidazole in the presence of strong bases to yield cyclic sulfamidates in one step, although frequently lower temperatures are required to prevent undesired reactions and lower yields are obtained. The reaction of sulfamate esters with hypervalent iodine reagents and various organometallic catalysts has proven to be a reliable method for the enantioselective preparation of cyclic sulfamidates; however, derivatives obtained in this way lack functionalization at the nitrogen atom, which is required for subsequent ring-openings as demonstrated both experimentally and computationally. The brilliant strategy developed by Nicolaou and co-workers to prepare diastereoand enantio-enriched sulfamidates from chiral vicinal diols has been expanded to epoxides; also, new Burgess-type reagents have been developed to install different substituents at the nitrogen atom in one single step. This method has been successfully coupled to the regioand stereoselective ring-opening of sulfamidates, even by attack at quaternary carbon centers by a plethora of nucleophiles including organometallic reagents. Consequently, the versatility of such building blocks for the preparation of bioactive compounds such as enantio-enriched αand β-amino acids and peptides with various substitution patterns, has bourgeoned in the last years. 6.01.12 Important Compounds and Application The benzothiazole scaffold presents relevant biomedical applications as an inhibitor and a biomarker. Vu and co-workers proposed a series of benzothiazole-based triamide derivatives with microsomal triglyceride transfer protein inhibition activity, among which compound 360 showed the highest inhibition capacity (Figure 11).255 Figure 11 1,2,3-Dithiazole-based heteroarenes represent a versatile building block expected to have broad applications in the biomedical field. Indeed, they look promising as multi-target directed ligands of Ser/Thr kinases.256 The synthesis of a series of related families of compounds (361-365) from dithiazole intermediates was described for the same biological application (Figure 12).257–261 49 Figure 12 1,2,3-Dithiazole-based N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methoxyaniline (366) was shown to reversibly inhibit melanin synthesis, thus showing potential for the treatment of pigmentation disorders such as melasma.262 1,2,3-Dithiazole derivatives have been shown to inactivate glutamine/amino acid transporter ASCT2, involved in amino acid metabolism. Selective inhibitors are fundamental to study this transport system and have implications in the development of antitumor compounds as ASCT2 is over-expressed in several tumors.263 Compound 367 showed the lowest IC50 value for ASCT2 inhibition among a library of nearly 50 analogs. Likewise, dithiazole and dithiazine provide the scaffold for a class of inhibitors of the human LAT1 transporter, which is overexpressed in several human cancers thus posing potential in the field of drug development. Compounds 368 and 369 showed the highest inhibition activity within a small synthetic library (Figure 13).264 Figure 13 Hilton and co-workers proposed 1,2,3-dithiazole-based molecules for biomedical applications for the inhibition of the feline immunodeficiency virus. The most potent compounds 69 and 370 are depicted in Figure 14.265 Figure 14 Marcos and co-workers proposed a synthetic route to 2-aminobenzothiazoles 374 from Herz compounds 372 which could be prepared from anilines 371.266 2-Aminobenzothiazoles 374 have remarkable biological activities as antitumor agents and inhibitors of leukotriene and thromboxane biosynthesis (Scheme 115). 50 Scheme 115 Prescher and co-workers have reported the use of Appel salt 32 in the synthesis of the benzo[d]thiazole-2-carbonitrile core of natural,267 alkynyl 375268 and nitro 376269 luciferin derivatives, as well as related imidazoline analogs 377 and 378270 as bioluminescent probes to analyze cell−cell contacts (Figure 15). Figure 15 Spirocyclic sulfamidate 379 was evaluated as a catalyst for the asymmetric epoxidation of alkenes with potassium peroxymonosulfate (Oxone®) and sodium bicarbonate in a mixture of acetonitrile and aqueous ethylenediaminetetraacetic acid disodium salt (Na2EDTA). In the case of epoxidation of E-stilbene 380, excellent conversion to epoxide 381 was achieved with an 87% enantiomeric excess. Catalytic asymmetric epoxidation of 1-phenylcyclohexene or E-ethyl cinnamate, gave much lower conversion values and enantiomeric excesses (Scheme 116) 117 Scheme 116 β-Amidophosphonate 382 was assayed for its in vitro cytotoxic activity towards several cell lines, exhibiting low cytotoxicity, even at high concentration levels (Figure 16).233 Figure 16 Cyclic sulfamidate 383, a bioisostere of trimethadione and phenytoin, showed a dosedependent anticonvulsant response in mice, provided protection against neurochemical 51 alterations, such as oxidative stress, and exhibited antidepressant-like effects, without affecting locomotor activity (Figure 17).103,271 Figure 17 Compound 384, which bears a cyclic sulfamidate and an oxazolidinone linked by a fluorobenzene ring, displayed antibacterial activity against Gram-positive bacterial strains resistant to methicillin and vancomycin (Figure 18).235 Figure 18 Compound 385 was evaluated as a conformationally restrained inhibitor of BACE-1, an aspartyl protease closely related to the formation of amyloid-beta peptide and, therefore, to Alzheimer’s disease. 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