Field of Invention

Disclosed herein is a process for the manufacture of a cationic and neutral fused N- heterocyclic ring systems.

Background

The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Bi- and tricyclic azole-thiazolines and related fused heterocycles are an important class of organic compounds that exhibit promising biological activities. They can be synthesized by reacting cyclic thioureas with α,ω-dihaloalkanes or derivatives, formally through double alkylation reactions (A, Figure 1). However, phase-transfer (PT) catalysis or microwave- assistance is often necessary to obtain satisfactory yields. Moreover, 2-mercaptoazoles are required, many of which are not easily available or difficult to prepare, which limits structural diversity.

Alternatively, such heterocycles can also be constructed from 2-phenylaminothiazoline via either direct intramolecular oxidative C-N bond formation (B1 , Figure 1) or intermolecular condensation with a-halogenoketones (B2, Figure 1). These methods suffer even more from limited versatility and scope. For example, the former can only give azole-thiazolines with a sp ² carbon. Respective seleno-derivatives are even rarer and obtained from organic isoselenocyanates via functionalized selenoureas. In most cases, these reagents have to be prepared in multiple steps making the overall procedure tedious, low yielding and less versatile. Analogous telluro compounds are unknown.

All carbon nucleophiles used to date are carbanions including Na ⁺ CHΞC- (or Li ⁺ ), R- (RX + Mg or Zn, Sm, In, etc.), and K ⁺ CF ₃ - (decarboxylation of CF ₃ COOK), which are highly reactive and difficult to handle. The application of neutral carbon nucleophiles remains unknown, which is surprising given the emergence of ubiquitous N-heterocyclic carbenes (NHCs) in all areas of chemistry. Thus, there remains a need for better synthetic methods to access these important structural scaffolds.

Summary of Invention

It is been surprisingly found that organic thiocyanates (R-SCN) can be used as a source of sulfur to access such compounds. In general, these compounds contain three reactive sites, i.e. sulfur, cyanide carbon, and an α-carbon. Selective attack can be achieved by appropriate choice of the nucleophile. Among various nucleophiles, only soft thiolates and carbon-based nucleophiles are known to regioselectively attack the soft sulphur atom affording disulfides and thioethers as synthetically important fragments.

In relation to our interest in the functionalization of NHCs, we herein report a new approach to fused azole-thiazolines. The versatile and simple one-pot procedure overcomes the aforementioned limitations and involves an intramolecular reaction of an in situ generated NHC with a thiocyanato group as the key step. Additional organic compounds (e.g. organic selenocyanates) can also be used in an analogous reaction sequence.

Aspects and embodiments of the invention will now be described by reference to the following numbered clauses.

1. A process for the manufacture of a cationic fused N-heterocyclic ring system, comprising reaction of a compound of formula I: where:

A comprises the depicted -N ⁺ =CH- moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

D represents OCN, SeCN, TeCN, CR ₁ R ₂ X or SCN;

X independently represents Br, Cl or I; n represents from 1 to 10; each Y independently represents O or S; o represents 0 to 5; each m, when present, independently represents from 1 to 5; each Ri and R ₂ independently represent H, C _1-6 alkyl, F, OH or SH; each R ₃ is independently C _1-6 alkyl, C _4-10 cycloalkyl, aryl, and heteroaryl, which four groups are unsubstituted or substituted by one or more of C _1-6 alkyl, C(O)R _4a , C(O)OR _4b , OR _4c , NR _4d R _4e , aryl and heteroaryl, which two latter groups are unsubstituted or substituted by one of more of C _1-6 alkyl, OR _5a , NR _5b R _5c ;

R _4a -R _4e and R _5a -R _5c are independently H or C _1-6 alkyl, with a base and with a material FF or only with a base to provide a compound of formula II: where:

A’ comprises the depicted -N ⁺ =C- moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

Z- represents an anion selected from X-, CN- or SCN ^· ; X, Y, n, o, m, R ₁ -R ₃ , R _4a -R _4e and R _5a -R _5c are as defined above; and E represents CR ₁ R ₂ , O, S, Se or Te (e.g. CR ₁ R ₂ or S) when the compound of formula I is reacted in the presence of a base without material FF, or E represents CH ₂ , O, S, Se or Te (e.g. O, S, Se orTe) when the compound of formula I is reacted in the presence of a base and the material FF, where the material FF is elemental sulphur, elemental selenium, or elemental tellurium.

2. A process for the manufacture of a cationic fused N-heterocyclic ring system, comprising reaction of a compound of formula I la: where:

A” comprises the depicted -N ⁺ =C-N- moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

X, Y, n, o, m, R ₁ -R ₃ , R _4a -R _4e and R _5a -R _5c are as defined in Clause 1;

E represents CR ₁ R ₂ , S, O, Se or Te; and R ₆ represents C _1-6 alkyl; with a base to provide a compound of formula III:

where

A’” comprises the depicted -N=C-N- moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

X, Y, n, o, m, R1-R ₃ , R _4a -R _4e and R _5a -R _5c are as defined in Clause 1; and E represents CR ₁ R ₂ , S, O, Se or Te.

3. The process according to Clause 1 or Clause 2, wherein, in the compound of formulae I to III and lla, o is 0.

4. The process according to any one of the preceding clauses, wherein, in the compound of formulae I to III and lla, A to A’” are each a 5- to 9-membered heterocyclic ring having one or two rings.

5. The process according to Clause 4, wherein A to A’” are each a 5- membered heterocyclic ring or a 9-membered bicyclic heterocyclic ring.

6. The process according to any one of the preceding clauses, wherein, in the compound of formulae I to III and lla, Ri and R2 are H.

7. The process according to any one of the preceding clauses, wherein, in the compound of formulae I to III and lla, n is from 2 to 4.

8. The process according to any one of the preceding clauses, wherein the base is an amine base or a mineral base, optionally wherein the base is sodium hydroxide. 9. The process according to any one of the preceding clauses, wherein D represents CR ₁ R ₂ X or SCN.

Drawings

A brief description of the drawings are provided below.

Figure 1 represents reaction schemes to generate compounds of interest according to literature procedures.

Figure 2 depicts a subset of synthesized thiazolino-azolium salts. The SCN counter anions are omitted for clarity. ^a Prepared stepwise from the bromoalkyl-azolium salts with calculated overall yields ^b Prepared in one-pot with yields obtained.

Figure 3 depicts a subset of synthesized cationic N,E-heterocyclic (E = C, S, Se, Te) salts.

Figure 4 depicts molecular structures of 2, 4, 5 and 12 showing 50% probability ellipsoids; SCN- anion and hydrogen atoms are omitted for clarity.

Figure 5 represents a mechanism for formation of thiazolino-azolium salt 1.

Figure 6 depicts molecular structure of 15 showing 50% probability ellipsoids, hydrogen atoms are omitted for clarity.

Description

The current invention provides an easier synthetic protocol to access bi- and tricyclic azole- thiazolines.

In a first aspect of the invention, there is provided a process for the manufacture of a cationic fused N-heterocyclic ring system, comprising reaction of a compound of formula I: where:

A comprises the depicted -N ⁺ =CH- moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents; D represents OCN, SeCN, TeCN, CR ₁ R ₂ X or SCN;

X independently represents Br, Cl or I; n represents from 1 to 10; each Y independently represents O or S;

0 represents 0 to 5; each m, when present, independently represents from 1 to 5; each R ₁ and R ₂ independently represent H, C _1-6 alkyl, F, OH or SH; each R ₃ is independently C _1-6 alkyl, C4-10 cycloalkyl, aryl, and heteroaryl, which four groups are unsubstituted or substituted by one or more of C _1-6 alkyl, C(0)R _4a , C(0)0R _4b , OR _4c , NR _4d R _4e , aryl and heteroaryl, which two latter groups are unsubstituted or substituted by one of more of C _1-6 alkyl, OR _5a , NR _5b R _5c

R _4a -R _4e and R _5a -R _5c are independently H or C _1-6 alkyl, with a base and with a material FF or only with a base to provide a compound of formula II:

where:

A’ comprises the depicted moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

Z- represents an anion selected from X-, CN ^_ or SCN-;

X, Y, n, o, m, R ₁ -R ₃ , R _4a -R _4e and R _5a -R _5c are as defined above; and

E represents CR ₁ R ₂ , O, S, Se or Te (e.g. CR ₁ R ₂ or S) when the compound of formula I is reacted in the presence of a base without material FF, or E represents CH ₂ , O, S, Se or Te (e.g. O, S, Se or Te) when the compound of formula I is reacted in the presence of a base and the material FF, where the material FF is elemental sulphur, elemental selenium, or elemental tellurium. In a second aspect of the invention, there is provided a process for the manufacture of a cationic fused N -heterocyclic ring system, comprising reaction of a compound of formula I la:

where:

A” comprises the depicted -N ⁺ =C-N- moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

Z- _, X, Y, n, o, m, R ₁ -R ₃ , R _4a -R _4e and R _5a -R _5c are as defined in Clause 1 ;

E represents CR ₁ R ₂ , S, O, Se or Te; and R ₆ represents C _1-6 alkyl; with a base to provide a compound of formula III: where

A’” comprises the depicted moiety and is a 5- to 14-membered heterocyclic ring system that is aromatic or partially unsaturated, and which may contain one or more further heteroatoms selected from O, S and N, which heterocyclic ring system may comprise one, two or three rings, where the ring system is unsubstituted or is substituted by one or more R ₃ substituents;

X, Y, n, o, m, R ₁ -R ₃ , R _4a -R _4e and R _5a -R _5c are as defined above; and E represents CR ₁ R ₂ , S, O, Se or Te.

In embodiments herein, the word “comprising” may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the word “comprising” may also relate to the situation where only the components/features listed are intended to be present (e.g. the word “comprising” may be replaced by the phrases “consists of’ or “consists essentially of”). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the word “comprising” and synonyms thereof may be replaced by the phrase “consisting of’ or the phrase “consists essentially of’ or synonyms thereof and vice versa.

The phrase, “consists essentially of” and its pseudonyms may be interpreted herein to refer to a material where minor impurities may be present. For example, the material may be greater than or equal to 90% pure, such as greater than 95% pure, such as greater than 97% pure, such as greater than 99% pure, such as greater than 99.9% pure, such as greater than 99.99% pure, such as greater than 99.999% pure, such as 100% pure.

As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

References herein (in any aspect or embodiment of the invention) to compounds of formulae I, II, lla and III includes references to such compounds perse, to tautomers of such compounds.

Compounds of formulae I, II, lla and III may contain double bonds and may thus exist as E (entgegen) and Z ( zusammen ) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

Compounds of formulae I, II, lla and III may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. Compounds of formulae I, II, I la and III may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

The term “halo”, when used herein, includes references to fluoro, chloro, bromo and iodo.

Unless otherwise stated, the term “aryl” when used herein includes C _6-14 (such as C _6-10 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. C _6-14 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Embodiments of the invention that may be mentioned include those in which aryl is phenyl.

Unless otherwise stated, the term “alkyl” refers to an unbranched or branched, acyclic or cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl)hydrocarbyl radical, which may be substituted or unsubstituted (with, for example, one or more halo atoms). Where the term “alkyl” refers to an acyclic group, it is preferably C _1-10 alkyl and, more preferably, C _1-6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl). Where the term “alkyl” is a cyclic group (which may be where the group “cycloalkyl” is specified), it is preferably C _3-12 cycloalkyl and, more preferably, C _5-10 (e.g. C _5-7 ) cycloalkyl.

Unless otherwise specified herein, a “heterocyclic ring system” may be 4- to 14-membered, such as a 5- to 10-membered (e.g. 6- to 10-membered), heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings. Examples of hetereocyclic ring systems that may be mentioned herein include, but are not limited to azetidinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4,5-dihydro-1/-/-maleimido, dioxanyl, dioxolanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, isothiaziolyl, isoxazolidinyl, isoxazolyl, morpholinyl, 1 ,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl, piperazinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl, pyrrolidinyl, pyrrolidinonyl, 3-sulfolenyl, sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl (e.g. 3,4,5,6-tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylenesulfoxide, tetrazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, thiophenethyl, triazolyl and triazinanyl.

In embodiments of the invention, the heterocyclic ring system may be selected from 1,2,3- triazolyl or, more particularly, imidazolyl, benzimidazolyl, pyridazinyl, 1,2,4-triazolyl, pyrazolyl, thiazolyl and benzothiazolyl. Said heterocyclic ring systems may be particularly suitable for ring system A in all aspects and embodiments of the invention featuring ring system A disclosed herein.

In further embodiments of the invention, the heterocyclic ring system may be selected from 1,2,3-triazolyl or, more particularly, imidazolyl, benzimidazolyl and 1,2,4-triazolyl. Said heterocyclic ring systems may be particularly suitable for ring system A” in all aspects and embodiments of the invention featuring ring system A” disclosed herein.

The heterocyclic ring system may be a heteroaryl ring system. The term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). Heteroaryl groups include those which have between 5 and 14 (e.g. 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H- 1.4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3- benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl,

1.2.4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1, 2,3,4- tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including

1.2.3.4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S-oxidised form. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl. Particularly preferred heteroaryl groups include monocylic heteroaryl groups.

In embodiments of the invention, the heteroaryl ring system may be selected from imidazolyl, benzimidazolyl, pyridazinyl, triazolyl, pyrazolyl, thiazolyl and benzothiazolyl. Said heteroaryl ring systems may be particularly suitable for ring system A in all aspects and embodiments of the invention featuring ring system A disclosed herein.

In other embodiments of the invention, the heteroaryl ring system may be selected from imidazolyl, benzimidazolyl and triazolyl. Said heteroaryl ring systems may be particularly suitable for ring system A” in all aspects and embodiments of the invention featuring ring system A” disclosed herein.

In embodiments of the invention, the compound of formula I may be selected from:

In embodiments of the invention, the compound of formula I la may be selected from:

Further embodiments of the invention that may be mentioned include those in which the compounds of formulae I, II, I la and III is isotopically labelled. However, other, particular embodiments of the invention that may be mentioned include those in which the compounds of formulae I, II, lla and III are not isotopically labelled.

The term "isotopically labelled", when used herein includes references to compounds of formulae I, II, lla and III in which there is a non-natural isotope (or a non-natural distribution of isotopes) at one or more positions in the compound. References herein to "one or more positions in the compound" will be understood by those skilled in the art to refer to one or more of the atoms of the compounds of formulae I, II, lla and III. Thus, the term "isotopically labelled" includes references to compounds of formulae I, II, lla and III that are isotopically enriched at one or more positions in the compound. The isotopic labelling or enrichment of the compounds of formulae I, II, lla and III may be with a radioactive or non-radioactive isotope of any of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and/or iodine. Particular isotopes that may be mentioned in this respect include ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁷ CI, ⁷⁷ Br, ⁸² Br and ¹²⁵ l). When the compounds of formulae I, II, I la and 11 Ms labelled or enriched with a radioactive or nonradioactive isotope, compounds of formulae I, II, I la and III that may be mentioned include those in which at least one atom in the compound displays an isotopic distribution in which a radioactive or non-radioactive isotope of the atom in question is present in levels at least 10% (e.g. from 10% to 5000%, particularly from 50% to 1000% and more particularly from 100% to 500%) above the natural level of that radioactive or non-radioactive isotope.

In the compounds of formulae I to III and I la, o may be 0.

In the compounds of formulae I to III and I la, A to A’” may each be a 5- to 9-membered heterocyclic ring having one or two rings.

In the compounds of formulae I to III and I la, A to A’” may each be a 5-membered heterocyclic ring or a 9-membered bicyclic heterocyclic ring.

In the compounds of formulae I to III and I la, Ri and R _å may be H.

In the compounds of formulae I to III and I la, n may be from 2 to 4.

In embodiments of the processes described herein, the base may be an amine base or a mineral base. For example, the base may be sodium hydroxide.

In compounds of formula I that may be mentioned herein, D may represent CR ₁ R ₂ X or SCN.

The compounds of formula II may also find application in ionic liquids or as liqand precursors. Bi- and tricyclic azole-thiazolines and related fused heterocycles are an important class of organic compounds that exhibit promising biological activities. Therefore, the methods used herein allow ready access to biologically interesting structural scaffolds, and so the methods may find use in drug discovery, as well as in process chemistry synthetic routes to active pharmaceutical compounds.

Examples

General considerations

All operations were performed without taking precautions to exclude air and moisture, and all solvents and chemicals were used as received. ¹ H and ¹³ C{ ¹ H} NMR spectra were recorded at 298 K on a Bruker ACF 300, DRX-400 spectrometer or AMX 500 spectrophotometer, and the chemical shifts (δ) were internally referenced to the residual solvent signals relative to tetramethylsilane ( ¹ H, ¹³ C). ESI mass spectra were measured using a Finnigan MAT LCQ spectrometer. Elemental analyses were performed on an ElementarVario Micro Cube elemental analyzer at the Department of Chemistry, National University of Singapore. As most of the products are hydroscopic solids or viscous oils, satisfactory elemental analyses were only achieved for a few compounds, and the best CHN values obtained are reported in the characterization results below. Salts 11, 12, 15, 16, 18, and 19 have been previously reported, and their ¹ H NMR spectra are in line with literature values; these salts were synthesized following General Synthetic Protocol 1 below (e.g by analogy to I3). The bromoalkylazolium salts for making compounds 17-30 were also synthesized following General Synthetic Protocol 1 below (e.g. by analogy to I3).

X-ray Diffraction Studies. Single crystals of 2, 4, 5, 12, 15 were obtained by slow evaporation of a concentrated solution in CH ₂ Cl ₂ /diethyl ether or CH ₂ Cl ₂ /hexane. X-ray data for them were collected with a Bruker AXS SMART APEX diffractometer, using Mo- or Cu-K _α radiation with the SMART suite of Programs. Data were processed and corrected for Lorentz and polarization effects with SAINT, and for absorption effect with SADABS. Structural solution and refinement were carried out with the SHELXTL suite of programs. The structure was solved by direct methods to locate the heavy atoms, followed by difference maps for the light, non-hydrogen atoms. All non-hydrogen atoms were generally given anisotropic displacement parameters in the final model. All H-atoms were put at calculated positions. A summary of the most important crystallographic data is given in Table A below.

Table A. Selected X-ray crystallographic data for complexes 2, 4, 5, 12, 15.

Table A (cont.)

General Synthetic Protocol 1

Procedure for the synthesis of bromoalkylazolium salts I Scheme 1: Preparation of bromoalkylazolium salts

Bromoalkyl azolium salts I was prepared by quarternization of alkyl- or arylazoles using a,w- dihaloalkanes ( Dalton Trans. 2011 , 40, 8788-8795). In a typical procedure, a mono-substituted azole (5 mmol, 1 equiv.) was dissolved in excess of dibromoalkane (ca., 100 mmol, 20 equiv.) and the reaction was heated at around 90°C for 24 hours. The excess dibromoalkane was recovered by vacuum distillation, and CH ₂ Cl ₂ was added to the residue. The resulting suspension was filtered through Celite. The filtrate was dried to give the bromoalkylazolium salts I as off- white solids.

General Synthetic Protocol 2A

Step 1: Procedure for the synthesis of thiocyanatoalkyl azolium salts II

Scheme 2. Preparation of thiocyanatoalkyl salts II.

The bromoalkyl azolium salts I (as prepared in General Synthetic Protocol 1) and KSCN (1.1 ~5 equivalents) were suspended in CH3CN and stirred overnight before the solvent was removed under reduced pressure (Scheme 2). CH ₂ Cl ₂ was added to the residue and filtered. Removal of the solvent from the filtrate afforded the thiocyanatoalkyl azolium salts II.

Step 2: Procedure for the cvclization to thiazolino-azolium salt

Scheme 3. Preparation of thiazolino-azolium salts. The thiocyanatoalkyl azolium salt II was dissolved in CH ₃ CN (10 mL ). To the mixture, an aqueous NaOH solution (10 mol% equivalent) was added. The reaction mixture was stirred at ambient temperature for 1 h, and then KSCN (5 equivalents) was added to replace the liberated cyanide anions (Scheme 3). The reaction mixture was stirred overnight before the solvent was removed under reduced pressure. CH ₂ CI ₂ was added to the residue and filtered. Removal of the solvent from the filtrate gave the products.

General Synthetic Protocol 2B

Procedure for the one-pot, two-step synthesis of cationic N.S-heterocvcles Alternatively, the products can be prepared in a one-pot, two-step reaction without isolation of thiocyanatoalkyl azolium salts II. The bromoalkyl azolium salts I were reacted with 5 equiv. KSCN followed by direct addition of 0.1 equiv. NaOH (Scheme 4). Full conversion of each step was monitored by ESI mass spectrometry. The work-up is the same as described for General Synthetic Protocol 2A affording the products.

Scheme 4. One-pot preparation of thiazolino-azolium salts.

Example 1 : Synthesis of cationic N-S-heterocycle 1 Scheme 5: Synthesis of compound 1. ^b Prepared in one-pot with yields obtained.

Compound 11

Compound 11 was prepared following General Synthetic Protocol 1 above using N-mesityl imidazole (931 mg, 5.00 mmol) and 1,4-dibromopropane. Yield: 78%.

Compound 111

The bromopropyl-imidazolium salt 11 (388 mg, 1.00 mmol) and KSCN (107 mg, 1.10 mmol) were suspended in CH ₃ CN (50 mL ) and stirred overnight before the solvent was removed under reduced pressure. CH ₂ CI ₂ (120 mL ) was added to dissolve the product and the resulting suspension was filtered and dried to afford the product 111 as a yellowish solid. Yield: 337 mg, 0.92 mmol, 92%. ¹ H NMR (300 MHz, CDCl ₃ ): 59.98 (s, 1 H, NCHN), 8.24 (s, 1 H, Imi-H), 7.18 (s, 1 H, Imi-H), 6.93 (s, 2 H, Ar-H), 4.85 (t, ³ J( H,H) = 7 Hz, 2 H, NCH ₂ ), 3.20 (t, ³ J(H,H) = 7 Hz, 2 H, SCH ₂ ), 2.54 (m, ³ J(H,H) = 7 Hz, 2 H, CH ₂ ), 2.26 (s, 3 H, CH ₃ ), 1.99 (s, 6 H, CH ₃ ). 1 ³ C{ ¹ H} NMR (101 MHz, CDCl ₃ ): 142.1 (NCHN), 138.6, 134.8, 131.2, 130.6, 124.13, 124.07 (Ar-C), 112.8 (SCN), 49.0 (NCH ₂ ), 31.5, 31.4 (CH ₂ ), 21.7, 18.4 (CH ₃ ). HRMS (ESI) m/z calcd. for C ₁₆ H _2O N ₃ S [M - Br] ⁺ 286.1371 ; found, 286.1372.

Compound 1

The thiocyanatopropyl-imidazolium salt 111 (37 mg, 0.10 mmol) and a NaOH aqueous solution (1 M, 10 μL) were mixed in CH ₃ CN (10 mL ) and stirred for 1 h before KSCN (49 mg, 0.50 mmol) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. CH ₂ Cl ₂ (80 ml.) was added and the resulting solution was filtered. Removal of the solvent from the filtrate yielded the product as an off-white solid. Yield: 28 mg, 0.09 mmol, 87%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.87 (s, 1 H, Imi-H), 7.12 (s, 1 H, Imi-H), 6.93 (s, 2 H, Ar-H), 4.59 (br-s, 2 H, NCH ₂ ), 3.45 (br-s, 2 H, SCH ₂ ), 2.50 (br-s, 2 H, CH ₂ ), 2.25 (s, 3 H, CH ₃ ), 1.95 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (126 MHz, CDCl ₃ ): 142.8 (NCN), 142.2, 135.7, 130.4, 129.0, 125.5, 122.0 (Ar-C), 47.3 (NCH ₂ ), 26.4 (SCH ₂ ), 22.4 (CH ₂ ), 21.5, 17.8 (CH ₃ ), SCN signal could not be detected. Anal. Calcd. for C16H19N3S2: C, 60.53; H, 6.03; N, 13.24. Found: C, 60.15; H, 5.79; N, 13.22. HRMS (ESI) m/z calcd. for C15H19N2S [M - SCN] ⁺ 259.1263; found, 259.1269.

Compound 1 was also prepared from compound 11 following General Synthetic Protocol 2B, which is an optimized one-pot procedure, without isolation of 111. Yield: 80%

Example 2: Synthesis of cationic N-S-heterocycles 2-5

Compounds 2-5 were prepared following General Synthetic Protocol 2A above. The compounds made, and their starting materials, are outlined in Table 1 below.

Table 1

Compound II2

This compound was prepared in analogy to 111 from I2 (374 mg, 1.00 mmol) and KSCN (486 mg, 5.00 mmol) as a pinkish solid. Yield: 326 mg, 0.99 mmol, 99%. ¹ H NMR (400 MHz, CDCl ₃ with 5 drops of CD ₃ CN): d 9.35 (br-s, 1 H, NCHN), 8.01 (br-s, 1 H, Imi-H), 7.25 (br-s, 1 H, Imi-H), 6.95 (br-s, 2 H, Ar-H), 4.94 (br-s, 2 H, NCH ₂ ), 3.73 (br-s, 2 H, SCH ₂ ), 2.27 (s, 3 H, CH ₃ ), 2.02 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCl ₃ with 5 drops of CD ₃ CN): 141.8 (NCHN), 138.1 , 134.7, 130.9, 130.2, 124.5, 124.4 (Ar-C), 111.7 (SCN), 50.0 (NCH ₂ ), 34.4 (SCH ₂ ), 21 .4, 17.8 (CH ₃ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for Ci5HisN ₃ S [M - SCN] ⁺ 272.1216; found, 272.1224.

Compound 2

Compound 2 was prepared in analogy to 1 from II2 (33 mg, 0.10 mmol), NaOH aqueous solution (1M, 10 μL) and KSCN (48 mg, 0.50 mmol) as a white solid. Yield: 28 mg, 0.09 mmol, 92%. ¹ H NMR (500 MHz, d ₄ -Methanol): <57.81 (s, 1 H, Imi-H), 7.58 (s, 1 H, Imi-H), 7.13 (s, 2 H, Ar-H), 4.76 (t, ³ J(H,H) = 8 Hz, 2 H, NCH ₂ ), 4.36 (t, ³ J(H,H) = 8 Hz, 2 H, SCH ₂ ), 2.36 (s, 3 H, CH ₃ ), 2.13 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (126 MHz, d ₄ -Methanol): 153.8 (NCN), 143.1, 136.1 (Ar-C), 133.6 (SCN ), 131.8, 131.0, 128.7, 121.9 (Ar-C), 51.1 (NCH ₂ ), 39.1 (SCH ₂ ), 21.2, 17.5 (CH ₃ ). Anal. Calcd. for CI ₅ HI ₇ N ₃ S ₂ : C, 59.37; H, 5.65; N, 13.85. Found: C, 59.33; H, 5.57; N, 13.73. HRMS (ESI) m/z calcd. for Ci ₄ Hi ₇ N ₂ S [M - SCN] ⁺ 245.1107; found, 245.1115.

Compound I3

A mixture of N-mesityl imidazole (931 mg, 5.00 mmol) and 1 ,4-dibromobutane (12 mL ) was stirred at 90 °C for one day. The excess 1 ,4-dibromobutane was recovered by vacuum distillation, and CH ₂ CI ₂ was added to the residue. The resulting suspension was filtered through Celite. The filtrate was dried and washed with diethyl ether (5 x 10 ml.) to afford the product as a white solid. Yield: 1.55 g, 3.85 mmol, 77%. 'H NMR (300 MHz, CDCI ₃ ): <5 10.48 (s, 1 H, NCHN), 7.71 (s, 1 H, Imi-H), 7.17 (s, 1 H, Imi-H), 7.01 (s, 2 H, Ar-H), 4.85 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.51 (t, ³ J( H,H) = 7 Hz, 2 H, SCH ₂ ), 2.34 (s, 3 H, CH ₃ ), 2.26-2.18 (m, 2 H, CH ₂ ), 2.08 (s, 6 H, CH ₃ ), 2.06-2.01 (m, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCI ₃ ): 140.6 (NCHN), 136.9, 133.7, 130.3, 129.3, 123.6, 123.0 (Ar-C), 48.6 (NCH ₂ ), 32.4, 28.8, 28.7 (CH ₂ ), 20.7, 17.2 (CH ₃ ). HRMS (ESI) m/z calcd. for CieH ₂₂ BrN ₂ [M - Br] ⁺ 321.0961 ; found, 321.0968.

Compound II3

This compound was prepared in analogy to 111 from I3 (137 mg, 0.34 mmol) and KSCN (35 mg, 0.36 mmol) as a yellowish solid. Yield: 118 mg, 0.31 mmol, 91%. ¹ H NMR (300 MHz, CDCI ₃ ): <59.96 (s, 1 H, NCHN), 8.16 (s, 1 H, Imi-H), 7.18 (s, 1 H, Imi-H), 6.94 (s, 2 H, Ar-H), 4.74 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.11 (t, ³ J(H,H) = 7 Hz, 2 H, SCH ₂ ), 2.28 (s, 3 H, CH ₃ ), 2.23-2.20 (m, 2 H, CH ₂ ), 2.00 (s, 6 H, CH ₃ ), 1.95-1.89 (m, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCI3): 141.8 (NCHN), 137.9, 134.7, 131.1, 130.4, 124.2, 124.0 (Ar-C), 112.9 (SCN), 49.7 (NCH ₂ ), 33.6, 29.1, 26.8 (CH ₂ ), 21.6, 18.1 (CH ₃ ). HRMS (ESI) m/z calcd. for CI ₇ H ₂₂ N ₃ S [M - Br] ⁺ 300.1529; found, 300.1540.

Compound 3

Compound 3 was prepared in analogy to 1 from II3 (148 mg, 0.39 mmol), NaOH aqueous solution (1 M, 39 μL) and KSCN (189 mg, 1.95 mmol) as an off-white solid. Yield: 124 mg, 0.37 mmol, 96%. ¹ H NMR (300 MHz, CDCI ₃ ): d 8.04 (s, 1 H, Imi-H), 7.17 (s, 1 H, Imi-H), 6.86 (s, 2 H, Ar-H), 4.57 (br-s, 2 H, NCH ₂ ), 2.89 (br-s, 2 H, SCH ₂ ), 2.17 (br-s, 5 H, CH ₂ and CH ₃ ), 2.01 (br-s, 2 H, CH ₂ ), 1.83 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (126 MHz, CDCI ₃ ): 144.5 (NCN), 141.5, 134.6 (Ar-C), 134.3 (SCN ), 130.9, 129.8, 127.2, 123.5 (Ar-C), 52.5 (NCH ₂ ), 33.8 (SCH ₂ ), 31.0, 26.1 (CH ₂ ), 21.2, 17.7 (CH ₃ ). HRMS (ESI) m/z calcd. for CI ₆ H ₂ IN ₂ S [M - SCN] ⁺ 273.1420; found, 273.1425.

Compound I4

1,2-Bis(bromomethyl)benzene (1.85 g, 7.00 mmol) was heated at 100 °C until it became molten and then N-mesityl imidazole (559 mg, 3.00 mmol) was added. The reaction mixture was stirred at 100 °C overnight. After cooling it to ambient temperature, dichloromethane (2 ml.) was added. The resulting solution was added to diethyl ether (150 mL) dropwise and a white solid was obtained which was washed with more diethyl ether (4 x 100 mL). The residue was then washed with acetone (2 x 20 mL). Removal of the solvent from the combined acetone washing afforded the product as a white solid. Yield: 293 mg, 0.65 mmol, 22%. ¹ H NMR (300 MHz, cfe-DMSO): d 9.59 (s, 1 H, NCHN), 8.04 (s, 1 H, Imi-H), 7.99 (s, 1 H, Imi-H), 7.59-7.33 (m, 4 H, Ar-H), 7.15 (s, 2 H, Ar-H), 5.73 (s, 2 H, NCH ₂ ), 4.95 (s, 2 H, BrCH ₂ ), 2.33 (s, 3 H, CH ₃ ), 2.04 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (75 MHz, d ₆ -DMSO): 140.2 (NCHN), 137.9, 136.6, 134.2, 132.7, 131.4, 131.1, 129.6, 129.5, 129.2, 124.2, 123.5 (Ar-C, two are coincident), 49.3 (NCH ₂ ), 31.7 (BrCH ₂ ), 20.5, 17.0 (CH ₃ ). HRMS (ESI) m/z calcd. for C ₂₀ H ₂₂ BrN ₂ [M - Br] ⁺ 369.0961 ; found, 369.0962.

Compound II4

This compound was prepared in analogy to 111 from I4 (293 mg, 0.65 mmol) and KSCN (316 mg, 3.25 mmol) as a pale-pink spongy solid. Yield: 233 mg, 0.57 mmol, 88%. ¹ H NMR (500 MHz, CDCl ₃ ): 59.45 (s, 1 H, NCHN), 7.57 (s, 1 H, Imi-H), 7.54-7.43 (m, 4 H, Ar-H), 7.16 (s, 1 H, Imi-H), 6.99 (s, 2 H, Ar-H), 5.99 (s, 2 H, NCH ₂ ), 4.52 (s, 2 H, SCH ₂ ), 2.32 (s, 3 H, CH ₃ ), 2.08 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (126 MHz, CDCI ₃ ): 142.2 (NCHN), 138.2, 135.6, 134.9, 133.1 ,

132.3, 131.6, 131.3, 130.8, 130.6, 124.0, 123.6 (Ar-C, two are coincident), 112.5 (SCN), 51.6 (NCH ₂ ), 36.1 (SCH ₂ ), 21.7, 18.3 (CH ₃ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C ₂₁ H ₂₂ N ₃ S [M - SCN] ⁺ 348.1529; found, 348.1525.

Compound 4

Compound 4 was prepared in analogy to 1 from II4 (89 mg, 0.22 mmol), NaOH aqueous solution (1 M, 22 μL) and KSCN (107 mg, 1.10 mmol) as an off-white solid. Yield: 80 mg, 0.21 mmol, 95%. ¹ H NMR (500 MHz, CDCI ₃ ): 58.32 (d, ³ J(H,H) = 2 Hz, 1 H, Imi-H), 7.77-7.75 (m, 1 H, Ar-H), 7.41-7.40 (m, 2 H, Ar-H), 7.35-7.33 (m, 1 H, Ar-H), 7.07 (d, ³ J(H,H) = 2 Hz, 1 H, Imi-H), 6.97 (s, 2 H, Ar-H), 6.07 (s, 2 H, NCH ₂ ), 4.75 (s, 2 H, SCH ₂ ), 2.32 (s, 3 H, CH ₃ ), 1.92 (s, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (126 MHz, CDCI ₃ ): 144.1 (NCN), 142.6, 136.8, 135.9, 133.8, 131.5,

131.3, 130.6, 130.4, 129.5, 129.1, 127.5, 122.0 (Ar-C), 53.5 (NCH ₂ ), 32.9 (SCH ₂ ), 21.8, 18.2 (CH ₃ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C _2O H ₂ IN ₂ S [M - SCN] ⁺ 321.1420; found, 321.1424.

Compound II5

This compound was prepared in analogy to 111 from I5 (396 mg, 1.00 mmol) and KSCN (486 mg, 5.00 mmol) as a pale-pink solid. Yield: 349 mg, 0.99 mmol, 99%. ¹ H NMR (300 MHz, CDCl ₃ ): d 10.23 (s, 1 H, NCHN), 7.98 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.64-7.28 (m, 8 H, Ar-H), 5.79 (s, 2 H, NCH ₂ Ph), 5.12 (br-s, 2 H, NCH ₂ ), 3.78 (br-s, 2 H, SCH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCl ₃ ): 143.2 (NCHN), 132.7, 132.3, 131.6, 130.0, 129.9, 129.0, 128.3, 128.1, 114.5, 113.9 (Ar-C), 112.3 (SCN), 52.5 (NCH ₂ Ph), 47.5 (NCH ₂ ), 34.1 (CH ₂ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C ₁₇ H ₁₆ N ₃ S [M - SCN] ⁺ 294.1059; found, 294.1064.

Compound 5

Compound 5 was prepared in analogy to 1 from II5 (232 mg, 0.66 mmol), NaOH aqueous solution (1 M, 66 μL) and KSCN (321 mg, 3.30 mmol) as an off-white solid. Analytically pure product was obtained by recrystallization from a concentrated MeOH solution. Yield: 184 mg, 0.56 mmol, 85%. ¹ H NMR (500 MHz, d ₄ -Methanol): d 7.80-7.79 (m, 1 H, Ar-H), 7.73-7.71 (m, 1 H, Ar-H), 7.60-7.54 (m, 2 H, Ar-H), 7.50-7.42 (m, 5 H, Ar-H), 5.58 (s, 2 H, NCH ₂ Ph), 4.77 (t, ³ J(H,H) = 8 Hz, 2 H, NCH ₂ ), 4.34 (t, ³ J(H,H) = 8 Hz, 2 H, SCH ₂ ). ¹³ C{ ¹ H} NMR (126 MHz, d ₄ -Methanol): 161.1 (NCN), 137.8, 133.6 (Ar-C), 133.5 (SCN ), 131.8, 130.5, 130.4, 130.1 ,

127.4, 126.9, 113.8, 113.4 (Ar-C), 51.9 (NCH ₂ Ph), 48.0 (NCH ₂ ), 39.1 (CH ₂ ). Anal. Calc, for C ₁₇ H ₁₅ N ₃ S ₂ : C, 62.74; H, 4.65; N, 12.91. Found: C, 62.37; H, 4.59; N, 12.71. HRMS (ESI) m/z calcd. for C ₁₆ H ₁₅ N ₂ S [M - SCN] ⁺ 267.0950; found, 267.0947.

Example 3: Synthesis of cationic N-S-heterocycles 6-13

Compounds 6-13 were prepared following General Synthetic Protocol 2B above. The compounds made, and their starting materials, are outlined in Table 2 below.

Compound 6

A mixture of bromopropyl-benzimidazolium bromide (41 mg, 0.10 mmol) and KSCN (49 mg, 0.50 mmol) was suspended in CH ₃ CN (10 mL ) and stirred overnight. An aqueous NaOH solution (1 M, 10 μL) was subsequently added and the suspension was stirred for another 12 h. Dichloromethane (50 mL) was added and the resulting solution was filtered. Removal of the solvent yielded the product as a yellowish solid. The yellowish solid was further purified by column chromatography using silica gel as a stationary phase and by eluting with a mixture of CH ₂ CI ₂ /CH ₃ OH (95:5 v/v) to obtain the pure compound. Yield: 32 mg, 0.10 mmol, 95%. ¹ H NMR (500 MHz, CD ₃ CN): d 7.74 (d, 1H, V(H,H) = 8 Hz, Ar-H), 7.67 (d, 1H, ³ J(H,H) = 8 Hz, Ar-H), 7.55 (m, 2H, Ar-H), 7.39-7.35 (m, 5H, Ar-H), 5.49 (s, 2H, NCH ₂ Ph), 4.44 (t, 2H, ³ J(H,H) = 6 Hz, NCH ₂ ), 3.55 (t, 2H, ³ J(H,H) = 6 Hz, SCH ₂ ), 2.53 (q, 2H, ³ J(H,H) = 6 Hz, CH ₂ ). ¹³ C{ ¹ H} NMR (125 MHz, CD ₃ CN): 151.6 (NCN), 134.1, 134.0, 132.3, 130.0, 129.7, 128.6, 127.2, 126.6, 112.6, 112.5 (Ar-C), 49.5 (NCH ₂ Ph), 44.3 (NCH ₂ ), 27.3 (SCH ₂ ), 21.8 (CH ₂ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C ₁₇ H ₁₇ N ₂ S [M - SCN] ⁺ 281.1107; found, 281.1107.

Compound I7

Compound I7 was synthesized in analogy to I3 from N- benzyl benzimidazole (1.04 g, 5.00 mmol) and 1 ,4-dibromobutane (12 mL) as a yellowish solid. Yield: 1.42 g, 3.35 mmol, 67%. ¹ H NMR (300 MHz, CDCI ₃ ): d 11.38 (s, 1 H, NCHN), 7.76 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.61-7.47 (m, 5 H, Ar-H), 7.33-7.30 (m, 3 H, Ar-H), 5.86 (s, 2 H, NCH ₂ Ph), 4.72 (br-s, 2 H, NCH ₂ ), 3.47 (t, ³ J(H,H) = 6 Hz, 2 H, BrCH ₂ ), 2.25 (br-s, 2 H, CH ₂ ), 2.02 (br-s, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCI ₃ ): 143.4 (NCHN), 133.3, 132.0, 131.8, 130.0, 129.8, 129.0, 127.9, 114.6, 113.8 (Ar-C), 52.2, 47.6 (NCH ₂ ), 33.5 (BrCH ₂ ), 29.8, 28.5 (CH ₃ ). HRMS (ESI) m/z calcd. for Ci ₈ H ₂₀ BrN ₂ [M - Br] ⁺ 343.0804; found, 343.0808.

Compound 7

Compound 7 was prepared in analogy to 6 from I7 (42 mg, 0.10 mmol), KSCN (49 mg, 0.50 mmol), NaOH aqueous solution (1 M, 10 μL) as a pale brown solid. Yield: 35 mg, 0.10 mmol, 98%. ¹ H NMR (400 MHz, CD ₃ CN): d 7.87 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.77 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.68-7.58 (m, 2 H, Ar-H), 7.39-7.32 (m, 5 H, Ar-H), 5.72 (s, 2 H, NCH ₂ Ph), 4.64 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.25 (t, ³ J(H,H) = 6 Hz, 2 H, SCH ₂ ), 2.31-2.27 (m, 2 H, CH ₂ ), 2.07-2.02 (m, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CD ₃ CN): 153.9 (NCN), 134.9, 134.2 (Ar-C), 132.9 (SCN ), 130.1, 129.7, 129.5, 128.5, 128.0, 127.9, 114.0, 113.7 (Ar-C), 51.2, 48.9 (NCH ₂ ), 34.6, 31.1, 25.7 (CH ₂ ). HRMS (ESI) m/z calcd. for CI ₈ HI ₉ N ₂ S [M - SCN] ⁺ 295.1263; found, 295.1273.

Compound 8

Compound 8 was prepared in analogy to 6 from 18 (167 mg, 0.50 mmol), KSCN (243 mg, 2.50 mmol), NaOH aqueous solution (1 M, 50 μL) as a pale-yellow solid. Yield: 128 mg, 0.49 mmol, 97%. ¹ H NMR (400 MHz, CD ₃ CN): <57.72-7.68 (m, 2 H, Ar-H), 7.58-7.55 (m, 2 H, Ar-H), 4.40 (t, ³ J(H,H) = 8 Hz, 2 H, NCH ₂ ), 3.79 (s, 3 H, CH ₃ ), 3.53 (t, ³ J( H,H) = 8 Hz, 2 H, SCNCH ₂ ), 2.50 (m, ³ J(H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CD ₃ CN): 151.3 (NCN) 133.7, 132.9, 127.0, 126.4, 112.3, 112.2 (Ar-C), 44.1 (NCH ₂ ), 32.0 (CH ₃ ), 27.1 (SCH ₂ ), 21.9 (CH ₂ ), SCN- signal could not be detected. Anal. Calc, for Ci ₂ Hi ₃ N ₃ S ₂ : C, 54.72; H, 4.98; N, 15.95. Found: C, 54.83; H, 4.67; N, 15.63. HRMS (ESI) m/z calcd. for C ₁₁ H ₁₃ N ₂ S [M - SCN] ⁺ 205.0794; found, 205.0796.

Compound 9

Compound 9 was prepared in analogy to 6 from I9 (113 mg, 0.30 mmol), KSCN (146 mg, 1.50 mmol), NaOH aqueous solution (1 M, 30 μL) as a pale-yellow solid. Yield: 89 mg, 0.29 mmol, 97%. ¹ H NMR (400 MHz, CDCl ₃ ): 5 7.65-7.63 (m, 1 H, Ar-H), 7.56-7.54 (m, 1 H, Ar-H), 7.45-7.38 (m, 2 H, Ar-H), 4.55 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.99 (d, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.61 (t, ³ J(H,H) = 6 Hz, 2 H, SCH ₂ ), 2.57 (m, V(H,H) = 6 Hz, 2 H, CH ₂ ), 2.22 (m, V(H,H) = 7 Hz, 1 H, CH), 0.91 (d, ³ J(H,H) = 7 Hz, 6 H, CH ₃ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCl ₃ ): 150.0 (NCN), 133.0, 131.9 (Ar-C), 131.2 (SCN ), 127.8, 126.9, 126.3, 112.1 (Ar-C), 53.3, 44.0 (NCH ₂ ), 28.8, 27.1, 21.9 (CH and CH ₂ ), 20.5 (CH ₃ ). HRMS (ESI) m/z calcd. for C ₁₄ H ₁₉ N ₂ S [M - SCN] ⁺ 247.1263; found, 247.1271.

Compound 110

Compound 110 was synthesized in analogy to I3 from N- methylpropionato benzimidazole (1.02 g, 5.00 mmol) and 1,3-dibromopropane (10 mL ) as a yellowish solid. Yield: 1.36 g, 3.35 mmol, 67%. ¹ H NMR (400 MHz, CDCl ₃ ): 5 10.79 (s, 1 H, NCHN), 7.83-7.78 (m, 2 H, Ar-H), 7.51-7.49 (m, 2 H, Ar-H), 4.82 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 4.73 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.47 (s, 3 H, CH ₃ ), 3.42 (t, ³ J(H,H) = 7 Hz, 2 H, BrCH ₂ ), 3.10 (t, ³ J(H,H) = 7 Hz, 2 H, COCH2), 2.54 (m, ³ J( H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCI ₃ ): <5 170.9 (CO), 143.3 (NCHN), 131.42, 131.37, 127.62, 127.57, 113.9, 113.5 (Ar-C), 52.6, 46.2, 43.4, 33.7, 32.2 (CH ₂ ), 30.1 (CH ₃ ). Anal. Calcd. for C ₁₄ H ₁₈ Br ₂ N ₂ O ₂ : C, 41.41 ; H, 4.47; N, 6.90. Found: C, 41.96; H, 4.79; N, 7.02. HRMS (ESI) m/z calcd. for C ₁₄ H ₁₈ Br ₂ N ₂ O ₂ [M - Br] ⁺ 325.0546; found, 325.0545.

Compound 10

Compound 10 was prepared in analogy to 6 from 110 (406 mg, 1.00 mmol), KSCN (486 mg, 5.00 mmol), NaOH aqueous solution (1 M, 100 μL) as an off-white solid. Yield: 329 mg, 0.98 mmol, 98%. ¹ H NMR (500 MHz, CDCI ₃ ): 67.74 (d, V(H,H) = 7 Hz, 1 H, Ar-H), 7.70 (d, V(H,H) = 7 Hz, 1 H, Ar-H), 7.51-7.46 (m, 2 H, Ar-H), 4.68 (t, ³ J( H,H) = 7 Hz, 2 H, NCH ₂ ), 4.60 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.79 (t, ³ J(H,H) = 7 Hz, 2 H, SCH ₂ ), 3.62 (s, 3 H, CH ₃ ), 3.00 (t, ³ J(H,H) = 7 Hz, 2 H, COCH ₂ ), 2.64 (m, ³ J( H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (126 MHz, CDCI ₃ ): 6171.0 (CO), 150.7 (NCN), 133.3, 131.6, 127.2, 126.7, 112.42, 112.38 (Ar-C), 53.0, 44.4, 42.0, 32.9, 27.7 (CH ₂ ), 22.0 (CH ₃ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C ₁₄ H ₁₇ N ₂ O ₂ S [M - SCN] ⁺ 277.1005; found, 277.1013.

Compound 111

Compound 111 was synthesized in analogy to I3 from phthalazine (651 mg, 5.00 mmol) and 1,3-dibromopropane (10 mL) as a pale-yellow solid. Yield: 1.49 g, 4.48 mmol, 90%. ¹ H NMR (300 MHz, CDCI ₃ ): 6 11.95 (s, 1 H, NCH), 10.00 (s, 1 H, NCH), 8.82 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 8.62 (d, V(H,H) = 8 Hz, 1 H, Ar-H), 8.36 (t, ³ J( H,H) = 8 Hz, 1 H, Ar-H), 8.25 (t, V(H,H) = 8 Hz, 1 H, Ar-H), 5.21 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.53 (t, ³ J(H,H) = 7 Hz, 2 H, BrCH ₂ ), 2.74 (m, ³ J(H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCI ₃ ): 155.2 (NCH), 152.5 (NCH), 140.1 , 136.9, 131.7, 129.0, 128.5, 128.4 (Ar-C), 63.0 (NCH ₂ ), 32.8 (BrCH ₂ ), 29.6 (CH ₂ ). HRMS (ESI) m/z calcd. for C ₁₁ H ₁₂ BrN ₂ [M - Br] ⁺ 251.0178; found, 251.0181.

Compound 11

Compound 11 was prepared in analogy to 6 from 111 (33 mg, 0.10 mmol), KSCN (49 mg, 0.5 mmol), NaOH aqueous solution (1 M, 10 μL) as a dark-brown solid. Yield: 24 mg, 0.09 mmol, 92%. ¹ H NMR (300 MHz, CDCI ₃ ): 68.36 (d, ³ J(H,H) = 7 Hz, 1 H, Ar-H), 8.12 (s, 1 H, NCH), 7.77-7.63 (m, 3 H, Ar-H), 4.29 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 2.74 (t, ³ J(H,H) = 7 Hz, 2 H, SCH ₂ ), 2.21 (m, ³ J(H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCI ₃ ): 159.9 (NCH), 138.4, 133.6, 132.2, 130.1 , 128.4, 127.2, 126.6 (Ar-C), 50.3 (NCH ₂ ), 36.5 (SCH ₂ ), 28.7 (CH ₂ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C ₁₁ H ₁₁ N ₂ S [M - SCN] ⁺ 203.0637; found, 203.0643.

Compound 112

Compound 112 was synthesized in analogy to I3 from 1 -benzyl triazole (796 mg, 5.00 mmol) and 1 ,3-dibromopropane (10 mL) as a yellowish solid. Yield: 1.17 g, 3.25 mmol, 65%. ¹ H NMR (400 MHz, CDCl ₃ ): d 11.60 (s, 1 H, NCHN), 9.09 (s, 1 H, NCHN), 7.54-7.51 (m, 2 H, Ar-H), 7.36-7.34 (m, 3 H, Ar-H), 5.68 (s, 2 H, NCH ₂ Ph), 4.72 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ), 3.47 (t, ³ J(H,H) = 7 Hz, 2 H, BrCH ₂ ), 2.60 (m, ³ J(H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCl ₃ ): 144.9 (NCHN), 143.7 (NCHN), 132.4, 130.3, 130.1 , 129.9 (Ar-C), 57.1, 48.0 (NCH ₂ ), 32.7 (BrCH ₂ ), 29.8 (CH ₂ ). HRMS (ESI) m/z calcd. for C ₁₂ H ₁₅ Br N ₃ [M - Br] ⁺ 280.0444; found, 280.0446.

Compound 12

Compound 12 was prepared in analogy to 6 from 112 (36 mg, 0.10 mmol), KSCN (49 mg, 0.5 mmol), NaOH aqueous solution (1 M, 10 μL) as a dark-brown solid. Yield: 23 mg, 0.08 mmol, 80%. ¹ H NMR (300 MHz, d ₆ -DMSO): 69.16 (s, 1 H, NCHN), 7.41-7.34 (m, 5 H, Ar-H), 5.43 (s, 2 H, NCH ₂ Ph), 4.31 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.50 (t, ³ J(H,H) = 6 Hz, 2 H, SCH ₂ ), 2.31 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, d ₆ -DMSO): 149.1 (NCN), 145.0 (NCHN), 132.8 (SCN ), 129.6, 128.9, 128.7, 128.4 (Ar-C), 53.0, 44.9 (NCH ₂ ), 26.6 (SCH ₂ ),

20.5 (CH ₂ ). HRMS (ESI) m/z calcd. for Ci ₂ Hi ₄ N ₃ S [M - SCN] ⁺ 232.0903; found, 232.0911.

Compound 113 N-phenyl pyrazole (721 mg, 5.00 mmol) and a CH ₃ CN (10 mL) solution of Nal (749 mg, 5.00 mmol) was added to 1,3-dibromopropane (10 mL). The mixture was stirred at 90 °C for one day. The excess 1 ,3-dibromopropane was recovered by vacuum distillation, and CH ₂ CI ₂ was added to the residue. The resulting suspension was filtered through Celite. The filtrate was dried and washed with ethyl acetate (3 x 10 mL) to afford the product as a red oil. Yield: 688 mg, 1.75 mmol, 35%. ¹ H NMR (400 MHz, CDCl ₃ ): d 8.75 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 8.26 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 7.80-7.73 (m, 5 H, Ar-H), 7.08 (t, ³ J(H,H) = 3 Hz, 1 H, CH), 4.63 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.41 (t, ³ J(H,H) = 6 Hz, 2 H, BrCH ₂ ), 2.38 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCl ₃ ): d 139.9, 139.7 (NCH), 134.0, 132.1, 131.8, 128.6 (Ar-C), 110.4 (CH), 50.7 (NCH ₂ ), 32.3 (BrCH ₂ ), 29.5 (CH ₂ ). HRMS (ESI) m/z calcd. for C ₁₂ H ₁₄ Br N ₂ [M - l] ⁺ 265.0335; found, 265.0336. Compound 13

Compound 13 was prepared in analogy to 6 from 113 (39 mg, 0.10 mmol), KSCN (49 mg, 0.5 mmol) and NaOH aqueous solution (1 M, 10 μL) as an orange oil. Yield: 24 mg, 0.09 mmol, 87%. ¹ H NMR (400 MHz, CDCl ₃ ): d 8.10 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 7.86-7.83 (m, 2 H, Ar-H), 7.65-7.60 (m, 3 H, Ar-H), 6.70 (d, ³ J(H,H) = 3 Hz, 1 H, CH), 4.41 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.46 (t, V(H,H) = 6 Hz, 2 H, SCH ₂ ), 2.55 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCl ₃ ): d 146.3 (NCH), 137.0 (NCS), 133.1, 132.4, 131.3, 128.9 (Ar-C), 107.6 (CH), 47.8 (NCH ₂ ), 25.0 (SCH ₂ ), 23.6 (CH ₂ ), SCN- signal could not be detected. HRMS (ESI) m/z calcd. for C ₁₂ H ₁₃ N ₂ S [M - SCN] ⁺ 217.0794; found, 217.0791.

Discussion

Previously, we reported the preparation of bromoalkylazolium salts by treatment of the respective azoles with an excess of a,w-dibromoalkanes (e.g. 11 , Scheme 5 above). Subsequent reaction with KSCN affords the respective thiocyanato-functionalized azolium precursors (e.g. 111). This substitution process can be easily monitored by ESI mass spectrometry, which revealed that generally one equiv. of KSCN is enough. In more difficult cases, an excess of up to five equiv. of KSCN were needed to accomplish full conversion. Subsequent reaction with NaOH leads to a ring-closure to give the bi/tricylic thiazolino-azolium salts, which can be isolated by simple filtration.

Surprisingly, lowering the amount of NaOH from stoichiometric to only 10 mol% still afforded the thiazolino-azolium salts in over 90% yields. Thus, only catalytic amounts of hydroxide are required to initiate deprotonation of the acidic NCHN protons of the first azolium molecules, while the remaining process is auto-catalytically accomplished by the released CN (vide infra) acting as a base instead. To provide further support for this notion, salt 111 was treated with an equimolar aqueous NaCN solution instead, which after stirring overnight also afforded product 1 in 76%.

Moreover, we found that prior isolation of the intermediate alkylthiocyanato azolium salts II is not necessary. As such, an optimized one-pot procedure was realized, using which the new heterocycles 1 and 2-13 (Figure 2; described in Example 3) derived from imidazole, benzimidazole, 1,2,4-triazole, pyrazole and phthalazine were conveniently prepared and isolated as white or pink solids from the respective bromoalkylazolium salts I. The formation of the N,S-heterocyclic salts 1-13 were straightforwardly confirmed by ESI mass spectrometry, in which base peaks for the molecular cations were observed in all cases. In their ¹ H NMR spectra, the most downfield NCHN proton characteristic for their precursors is absent, which hints to intermediate carbene formation. The resonances of the SCH ₂ protons are shifted upfield in comparison to those of the BrCH ₂ in the starting materials. Another characteristic feature is the downfield shifts of NCN carbon atoms observed in their ¹³ C NMR spectra upon C-S bond formation. Single crystal X-ray diffraction analyses of the representatives 2, 4, 5 and 12 further confirm the expected compositions (Figure 4).

As mentioned above, this new methodology is supposed to occur via base-assisted in situ NHC formation followed by intramolecular nucleophilic attack of the carbene carbon at the sulphur atom of the thiocyanate tether leading to S-CN bond fission and elimination of one CN ^~ anion. After C _carbene -S bond formation, additional anion metathesis was conducted with excess KSCN (Figure 5). For compounds 11 and 13 (described in Example 3), intermediate occurrence of phthalazinylidenes and pyrazolinylidenes as non-classical NHCs is anticipated.

To provide evidence for the cyanide elimination, the resulting reaction mixture was treated with FeSO _4· -7H ₂ O. The Fe" ion captures the eliminated CN- anions forming the yellowish Na ₄ [Fe(CN) ₆ ] complex. Subsequent addition of Fe ₂ Cl ₃ led to the precipitation of dark blue Fe ₄ [Fe(CN) ₆ ] ₃ (Prussian Blue).

General Synthetic Protocol 3A

Procedure using N-oropionato-N’-thiocvanatoalkyl azolium salts

Neutral heterocycles can be prepared by using N-propionato azolium salts. The N-propionate protecting group is removed upon treatment with a base to give neutral azole-thiazolines.

Scheme 6. Preparation of neutral azole-thiazoline. The N-propionato-N’-thiocyanatoalkyl azolium salt II (prepared as described in General Synthetic Protocol 2A, step 1) was dissolved in CH ₃ CN (10 mL ). An aqueous NaOH solution (1.1 equivalent) was added, and the reaction mixture was stirred at ambient temperature for 4 h and then heated at 70 °C overnight. After the solvent was removed in vacuum, the product was washed out using diethyl ether (5 x 10 mL ).

General Synthetic Protocol 3B

Procedure using using N-propionato-N’-bromoalkyl azolium salts in 1-pot, 2-step Alternatively, neutral N,S heterocycles can be prepared in an one-pot, 2-step reaction by reacting the N-propionato-N’-bromoalkyl azolium salt with 5 equiv. KSCN followed by direct addition of 1.1 equiv. NaOH. Full conversion of each step was monitored by ESI mass spectrometry. The work-up is the same as described in General Synthetic Protocol 3A above to give the product.

Scheme 7. Preparation of neutral azole-thiazoline.

Example 4: Synthesis of neutral N,S-heterocycle 14

Scheme 8: Synthesis of neutral N,S-heterocycle 14 Compound 10 (34 mg, 0.10 mmol) was mixed with an aqueous NaOH solution (1 M, 100 μL) in CH ₃ CN (5 mL ), and the reaction mixture was stirred at 70 °C overnight. After the solvent was removed in vacuum, the product 14 was washed out by diethyl ether (5 x 10 ml.) and dried as a yellowish solid. Yield: 18 mg, 0.10 mmol, 97%. ¹ H NMR (300 MHz, CDCI ₃ ): 57.59 (d, ³ J(H,H) = 7 Hz, 1 H, Ar-H), 7.21-7.19 (m, 3 H, Ar-H), 4.17 (t, ³ J(H,H) = 7 Hz, 2 H, NCH ₂ ),

3.22 (t, V(H,H) = 7 Hz, 2 H, SCH ₂ ), 2.45 (m, ³ J(H,H) = 7 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCl ₃ ): d 147.6 (NCN), 141.6, 135.7, 123.5, 122.5, 118.0, 108.7 (Ar-C), 43.2 (NCH ₂ ), 26.4 (SCH ₂ ), 23.7(CH ₂ ). HRMS (ESI) m/z calcd. for C ₁₀ H ₁₀ N ₂ S [M + H] ⁺ 191.0637; found, 191.0642. Same as in literature (Molecules 2016, 21, 12-23).

Compound 14 was also prepared following General Synthetic Protocol 3B above from compound 110. Yield: 95%

Example 5: Synthesis of neutral N,S-heterocycles 15-16

Compounds 15-16 were prepared following General Synthetic Protocol 3B above. The compounds made, and their starting materials, are outlined in Table 3 below.

Table 3

Compound 115

Compound 115 was synthesized in analogy to I4 from 1,2-bis(bromomethyl)benzene (1.85 g, 7.00 mmol) and N-methylpropionato imidazole (154 mg, 1.00 mmol) as a yellow solid. The yellow solid was further purified by column chromatography using silica gel as a stationary phase and by eluting with a CH ₂ Cl ₂ /CH3OH mixture (90:10 v/v) to obtain the pure compound.Yield: 163 mg, 0.39 mmol, 39%. ¹ H NMR (400 MHz, CD ₃ CN): d 9.64 (br, 1 H, NCHN), 7.72-7.66 (m, 1 H, Imi-H), 7.55-7.53 (m, 1 H, Imi-H), 7.47 (br, 1 H, Ar-H), 7.37 (br, 3 H, Ar-H), 5.71 (s, 2 H, NCH ₂ ), 4.81 (s, 2 H, BrCH ₂ ), 4.48-4.45 (m, 2H, NCH ₂ ), 3.60 (s, 3 H,

CH ₃ ), 2.99-2.96 (m, 2H, COCH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CD ₃ CN): <5 171.5 (CO), 137.92, 137.87 (Ar-C), 133.2 (NCHN), 132.2, 131.3, 130.7, 130.4, 123.9, 123.2 (Ar-C), 52.6, 50.5, 46.0, 34.8 (CH ₂ ), 32.2 (CH ₃ ). HRMS (ESI) m/z calcd. for C ₁₅ H ₁₈ BrN ₂ O ₂ [M - Br] ⁺ 337.0546; found, 337.0545.

Compound 15 Compound 115 (84 mg, 0.20 mmol) and KSCN (97 mg, 1.00 mmol) were suspended in CH ₃ CN (10 mL ) and stirred overnight. An aqueous solution of NaOH (1 M, 220 μL) was subsequently added, and the resulting mixture was stirred at ambient temperature for 4 h and then heated at 70 °C overnight. After the solvent was removed in vacuum, the product 15 was washed out with ether (5 x 10 ml.) and dried as a white solid. The white solid was purified by recrystallization from CHCI3. Yield: 32 mg, 0.16 mmol, 80%. Single crystal was obtained by slow evaporation of a saturated solution in CH ₂ CI ₂ /diethyl ether. ¹ H NMR (500 MHz, CDCI3): d 7.38-7.32 (m, 2 H, Ar-H), 7.30-7.29 (m, 2 H, Imi-H), 6.97-6.96 (m, 2 H, Ar-H), 5.21 (s, 2

H, IMCH2), 4.29 (s, 2 H, SCH2). ¹³ C{ ¹ H} NMR (126 MHz, CDCI3): d 139.9 (NCN), 138.1 , 134.7, 130.3, 129.8, 129.5, 128.9, 128.5, 122.6 (Ar-C), 50.9 (NCH ₂ ), 32.7 (SCH ₂ ). Anal. Calcd. for C ₁₁ H ₁₀ N ₂ S: C, 65.32; H, 4.98; N, 13.85. Found: C, 65.48; H, 5.06; N, 13.83. HRMS (ESI) m/z calcd. for C ₁₁ H ₁₀ N ₂ S [M + H] ⁺ 203.0637; found, 203.0639.

Compound 116

Compound 116 was synthesized in analogy to I3 from 1-methylpropionato triazole (776 mg, 5.00 mmol) and 1,3-dibromopropane (10 mL) as a yellowish and sticky solid. Yield: 696 mg,

I.95 mmol, 39%. ¹ H NMR (300 MHz, CDCl ₃ ): d 11.31 (s, 1 H, NCHN), 9.11 (s, 1 H, NCHN), 4.85 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 4.75 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.69 (s, 3 H, CH ₃ ), 3.54 (t, ³ J(H,H) = 6 Hz, 2 H, BrCH ₂ ), 3.13 (t, ³ J(H,H) = 6 Hz, 2 H, COCH ₂ ), 2.65 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (75 MHz, CDCI ₃ ): d 170.9 (CO), 144.9, 144.5 (NCHN), 53.2, 49.1, 48.0, 33.0, 32.8 (CH ₂ ), 30.0 (CH ₃ ). HRMS (ESI) m/z calcd. for C ₉ H ₁₅ BrN ₃ O ₂ [M - Br] ⁺ 276.0342; found, 276.0346.

Compound 16

Compound 16 was prepared in analogy to 15 from 116 (71 mg, 0.2 mmol), KSCN (97 mg, 1.00 mmol) and a NaOH aqueous solution (1 M, 220 μL) as a white solid. Yield: 27 mg, 0.19 mmol, 94%. ¹ H NMR (400 MHz, CDCI ₃ ): d 8.06 (s, 1 H, NCHN), 4.10 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.13 (t, ³ J(H,H) = 6 Hz, 2 H, SCH ₂ ), 2.31 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDsCN): d 146.4 (NCN), 144.0 (NCHN), 44.0 (NCH ₂ ), 26.4 (SCH ₂ ), 23.9 (CH ₂ ). Anal. Calcd. for C ₅ H ₇ N ₃ S: C, 42.53; H, 5.00; N, 29.76. Found: C, 42.90; H, 5.04; N, 30.00. HRMS (ESI) m/z calcd. for C ₅ H ₇ N ₃ S [M + H] ⁺ 142.0433; found, 142.0432.

Discussion The tricyclic imidazole 15 and the bicyclic triazole 16 with different backbones were successfully prepared and isolated in satisfactory yields. Compounds 14 and 15 were isolated as white solids, while 16 was obtained as a yellowish oil. They are all well-soluble in common organic solvents. Additionally, the formation of tricyclic 15 was unambiguously confirmed by X-ray diffraction analysis of a single crystal (Figure 6).

Scheme 9. Formation of SCN-propyl-pyrazole.

Similar reaction performed with the N-methylpropionato-N’-bromopropyl-pyrazolium salt, however, afforded no pyrazole-thiazoline possibly due to the lower acidity of the NCH proton. Here, only elimination occurred leading to the formation of the neutral N- propylthiocyanatopyrazole 31 even with stronger bases such as NaH and KHMDS (Scheme 9).

Compound 131 was synthesized in analogy to I3 from N- methylpropionato pyrazole (771 mg, 5.00 mmol) and 1 ,3-dibromopropane (10 mL) as a colorless oil. Yield: 1.42 g, 4.00 mmol, 80%. ¹ H NMR (400 MHz, CDCI ₃ ): d 8.79 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 8.73 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 6.74 (t, ³ J(H,H) = 3 Hz, 1 H, CH), 5.02-4.99 (m, 4 H, NCH ₂ ), 3.61 (s, 3 H, CH ₃ ), 3.53 (t, ³ J(H,H) = 6 Hz, 2 H, BrCH ₂ ), 3.17 (t, ³ J(H,H) = 6 Hz, 2 H, COCH ₂ ), 2.53 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCI ₃ ): <5170.9 (CO), 138.98, 138.88 (NCH), 108.9 (CH), 53.1, 49.7, 46.7, 34.5, 32.8 (CH ₂ ), 29.7 (CH ₃ ). HRMS (ESI) m/z calcd. for C ₁₀ H ₁₆ BrN ₂ O ₂ [M - Br] ⁺ 275.0390; found, 275.0389.

Compound 1131 was prepared in analogy to 111 from 131 (356 mg, 1.00 mmol) and KSCN (486 mg, 5.00 mmol) as a pinkish oil. Yield: 291 mg, 0.93 mmol, 93%. ¹ H NMR (400 MHz, CD ₃ CN): <58.28 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 8.26 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 6.78 (t, ³ J(H,H) = 3 Hz, 1 H, CH), 4.70 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 4.62 (t, ³ J(H,H) = 6 Hz, 2 H, NCH ₂ ), 3.64 (s, 3 H, CH ₃ ), 3.15 (t, ³ J(H,H) = 6 Hz, 2 H, SCNCH ₂ ), 3.02 (t, ³ J(H,H) = 6 Hz, 2 H, COCH ₂ ), 2.41 (m, ³ J{ H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CD ₃ CN): <5 171.3 (CO), 139.1, 138.5 (NCH), 113.0 (SCN), 109.0 (CH), 52.8, 49.1, 46.5, 33.8, 30.9 (CH ₂ ), 30.2 (CH ₃ ), SCN signal could not be detected. HRMS (ESI) m/z calcd. for C11H16N3O2S [M - SCN] ⁺ 254.0958; found, 254.0965.

Synthesis of Compound 31. Compound 1131 (81 mg, 0.26 mmol) was dissolved in CH ₃ CN and an aqueous solution of NaOH (1 M, 286 μL) was added. The suspension was stirred at ambient temperature for four hours and then heated at 80 °C overnight. After the solvent was removed in vacuum, the product was washed out by ether (5 x 10 mL ) as a colorless oil (41 mg, 0.25 mmol, 95%). ¹ H NMR (400 MHz, CDCI ₃ ): <57.56 (d, ³ J( H,H) = 3 Hz, 1 H, NCH), 7.45 (d, ³ J(H,H) = 3 Hz, 1 H, NCH), 6.30 (t, ³ J(H,H) = 3 Hz, 1 H, CH), 4.37 (t, ³ J(H,H) = 6 Hz, 2 H, NCH2), 2.91 (t, ³ J(H,H) = 6 Hz, 2 H, SCNCH2), 2.42 (m, ³ J(H,H) = 6 Hz, 2 H, CH ₂ ). ¹³ C{ ¹ H} NMR (101 MHz, CDCI ₃ ): d 140.0, 130.6 (NCH), 112.4 (SCN), 106.8 (CH), 49.7 (NCH ₂ ), 31.5 (SCH ₂ ), 31.0 (CH ₂ ). Anal. Calcd. for C ₇ H ₉ N ₃ S: C, 50.28; H, 5.42; N, 25.13. Found: C, 49.92; H, 5.31 ; N, 25.49. HRMS (ESI) m/z calcd. for C ₇ H ₉ N ₃ S [M + H] ⁺ 168.0590; found, 168.0596.

General Synthetic Protocol 4

Procedure for the synthesis of cationic N.E-heterocvcles (E = C, S, Se, Te;)

Scheme 10. One-pot preparation of cationic N, E-heterocycles (E = C, S, Se, Te)

A Schlenk-tube was charged with the respective bromo-functionalized azolium salt I (1 mmol), base (tributylamine or K ^t OBu, 1.1 mmol) and elemental chalcogen (only for S, Se, Te; 5 mmol) in anhydrous acetonitrile (5 mL ). The Schlenk-tube was degassed, filled with argon, and heated at up to the temperature required. Reaction progress was then monitor using TLC or ESI-MS after 10 h. After the reaction, the excess elemental chalcogen was removed by filtration, and solvent of the filtrate was removed. The solid obtained was washed with THF (3 x 5 mL ) and purified by column chromatography on silica.

Example 6: Synthesis of cationic N, E-heterocycles 17-30 Compounds 17-30 (Figure 3) were prepared following General Synthetic Protocol 4 above. The detailed procedure for synthesizing each compound is described below.

Compound 17a. 4-mesityl- 1-bromopropyl-1 ,2,4-triazolium bromide (389 mg, 1 mmol; 117) was stirred with tributyl amine (260 μL, 1.1 mmol) in acetonitrile (5 ml.) at 70 °C for 14 h. The solvent of the filtrate was removed under reduced pressure and the solid obtained was washed with tetrahydrofurane (3 x 5 mL ). The compound was obtained as an off-white solid after precipitated out from its solution in methanol using diethylether. Yield: 220 mg (0.71 mmol, 71%). ¹ H-NMR (CDCl ₃ , 500 MHz): <5 = 8.71 (s, 1 H, NCHN), 7.00 (s, 2 H, Ar-H), 4.79 (t, 2 H, NCH ₂ ), 3.39 (t, 2 H, CH ₂ ), 3.16 (m, 2 H, CH ₂ CH ₂ CH ₂ ), 2.32 (s, 3 H, CH ₃ ), 2.18 (s, 6 H, CH ₃ ). ¹³ C-NMR (CDCl ₃ , 126.7 MHz): <5 = 159.9 (NCN), 149.3 (NCN), 142.7, 135.4, 130.8, 127.4 (Ar- C), 51.3 (NCH ₂ ), 26.3 (CH ₂ ), 23.7 (CH ₂ ), 21.7 (CH ₃ ), 19.2 (CH ₃ ). Anal, calcd. for C ₁₄ H ₁₈ BrN ₃ : C, 54.56; H, 5.89; N, 13.63; found: C, 54.17; H, 5.84; N, 13.54; MS (ESI, m/z)\ calcd. for [M - Br] ⁺ , C ₁₄ H ₁₈ N ₃ , m/z 228; found, m/z 228.

Compound 17b. The salt was synthesized in a similar pathway with 17a using 4-cyclohexyl- 1-bromopropyl 1 ,2,4-triazolium bromide (350 mg, 1 mmol; 118) and tributyl amine (260 μL, 1.1 mmol). Yield: 180 mg (0.66 mmol, 66%). ¹ H-NMR (CDCl ₃ , 500 MHz): <5 = 9.13 (s, 1 H, NCHN), 4.55-4.50 (m, 1 H, NCH), 4.46 (t, ³ J _H-H = 7.4 Hz, 2 H, NCH ₂ ), 3.60 (t, ³ J _H-H = 7.5 Hz, 2 H, CH ₂ ), 3.02 (m, 2 H, CH ₂ ), 2.29 (d, 2 H, CH ₂ ), 1.87 (d, 2 H, CH ₂ ), 1.76-1.68 (m, 3 H, CH _2, CH ₂ ), 1.50- 1.41 (m, 2 H, CH ₂ ), 1.29-1.20 (m, 1 H, CH ₂ ). ¹³ C-NMR (CDCl ₃ , 126.7 MHz): d = 158.2 (NCN), 147.9 (NCN), 59.7, 49.6, 33.3, 25.9, 25.4, 25.1, 24.5 (CH ₂ ). Anal, calcd. for CnHi ₈ BrN ₃ : C, 48.54; H, 6.67; N, 15.44; found: C, 47.44; H, 6.63; N, 14.70. MS (ESI, m/z): calcd for [M-Br] ⁺ , C ₁₁ H ₁₈ N ₃ , m/z 192; found, m/z 192.

Compound 18a. A Schlenk tube was charged with 4-mesityl-1-bromopropyl-1,2,4-triazolium bromide (389 mg, 1 mmol; 117), elemental sulfur (160 mg, 5 mmol), tributyl amine (260 μL, 1.1 mmol) and anhydrous acetonitrile (5 mL ). The mixture was then degassed and filled with innert argon and stirred at 70 °C for 14 h. The solid was removed using a sintered glass funnel and washed with methanol (3 x 5 mL ). The solvent of the filtrate was removed under reduced pressure and the solid obtained was washed with tetrahydrofurane (3 x 5 mL ). The compound was then purified by silica gel column chromatography using DCM/MeOH (v/v 10/0.5) as eluent. Yield: 250 mg (0.74 mmol, 74%). ¹ H-NMR (CDCl ₃ , 500 MHz): d = 8.61 (s, 1 H, NCHN), 6.98 (s, 2 H, Ar-H), 4.68 (t, 2 H, NCH ₂ ), 3.65 (t, 2 H, SCH ₂ ), 2.64 (br,m, 2 H, CH ₂ CH ₂ CH ₂ ), 2.30 (s, 3 H, CH ₃ ), 2.04 (s, 3 H, CH ₃ ). ¹³ C-NMR (CDCl ₃ , 126.7 MHz): d = 151.5 (NCN), 143.4 (NCN), 143.1 , 135.9, 130.8, 125.9 (Ar-C), 49.6 (NCH ₂ ), 27.7 (CH ₂ ), 22.7 (CH ₂ ), 21.7 (CH ₃ ), 18.2 (CH ₃ ). Anal, calcd. for Ci ₄ Hi ₈ BrN ₃ S: C, 49.42; H, 5.33; N, 12.35; found: C, 49.55; H, 6.00; N, 12.45; MS (ESI, m/z): calcd for [M - Br], C ₁₄ H ₁₈ N ₃ S, m/z 260; found, m/z 260.

Compound 18b. The compound was synthesized in a similar procedure with 18a using 4- cyclohexyl-1-bromopropyl-1 ,2,4-triazolium bromide (355 mg, 1 mmol; 118), elemental sulfur (160 mg, 5 mmol) and tributyl amine (260 μL, 1.1 mmol). Yield: 240 mg (0.80 mmol, 80%). ¹ H- NMR (CDCl ₃ , 500 MHZ): δ = 9.03 (s, 1 H, NCHN), 4.66 (t, ³ J _H-H = 5.9 Hz, 2 H, NCH ₂ ), 4.10 (m, 1 H, NCH), 3.83 (t, ³ J _H-H = 5.4 Hz, 2 H, CH ₂ ), 2.67-2.63 (m, 2 H, CH ₂ ), 2.25 (d, 2 H, CH ₂ ), 1.96 (d, 1 H, CH ₂ ), 1.92-1.84 (m, 2 H, CH ₂ ), 1.76-1.70 (m, 2 H, CH ₂ ), 1.48-1.40 (m, 2 H, CH ₂ ), 1.37-1.32 (m, 1 H, CH ₂ ). ¹³ C-NMR (CDCl ₃ , 126.7 MHz): <5 = 149.4 (NCN), 141.8 (NCN), 59.3, 49.4, 32.8, 27.9, 25.8, 25.0, 23.1 (CH ₂ ). Anal, calcd. for C ₁₁ H ₁₈ BrN ₃ : C, 43.43; H, 5.96; N, 13.81 ; S, 10.54. found: C, 42.87; H, 5.93; N, 13.56; S, 9.89. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₁ H ₁₈ N ₃ S, m/z 224; found, m/z 224.

Compound 19a. The salt was synthesized following the same procedure as for 18a using 4- mesityl-1-bromopropyl-1 ,2,4-triazolium bromide (347 mg, 1 mmol; 117), elemental selenium (400 mg, 5 mmol) and tributyl amine (260 μL, 1.1 mmol). After reaction, the solid was removed using a sintered glass funnel and washed with methanol (3 x 5 mL ). The solvent of the filtrate was removed under reduced pressure and the solid obtained was washed with tetrahydrofurane (3 x 5 mL ) to afford pure 19a as a white solid. Yield: 330 mg (0.85 mmol, 85%). ¹ H-NMR (CD ₃ CN, 500 MHz): <5 = 8.70 (s, 1 H, NCHN), 7.17 (s, 1 H, Ar-H), 4.47 (t, 2 H, NCH ₂ ), 3.52 (t, 2 H, CH ₂ Se), 2.66 (m, 2 H, CH ₂ CH ₂ CH ₂ ), 2.37 (s, 3 H, CH ₃ ), 2.04 (s, 6 H, CH ₃ ). ¹³ C-NMR (CD ₃ CN, 126.7 MHz): <5 = 156.0 (NCN), 144.7 (NCN), 143.7, 136.6, 131.1 (2C) (Ar- C), 51.1 (NCH ₂ ), 24.5 (CH ₂ Br), 24.2 (CH ₂ CH ₂ CH ₂ ), 21.2 (CH ₃ ), 17.8 (CH ₃ ). Anal, calcd. for C ₁₄ H ₁₈ BrN ₃ Se: C, 43.43; H, 4.69; N, 10.85; found: C, 43.34; H, 4.60; N, 10.86; MS (ESI): calcd. for [M - Br] ⁺ , Ci ₄ Hi ₈ N ₃ Se, m/z 308; found, m/z 308.

Compound 19b. The compound was synthesized following the procedure for 19a using 4- cyclohexyl-1-bromopropyl-1 ,2,4-triazolium bromide (355 mg, 1 mmol; 118). Yield: 275 mg (0.78 mmol, 78%). ¹ H-NMR (CDCl ₃ , 500 MHz): <5 = 10.18 (s, 1 H, NCHN), 5.18 (t, ³ J _H-H = 5.7 Hz, 2 H, NCH ₂ ), 4.87 (m, 1 H, NCH), 4.34 (t, ³ J _H-H = 5.4 Hz, 2 H, CH ₂ ), 3.37-3.33 (m, 2 H, CH ₂ ), 2.82 (d, 2 H, CH ₂ ), 2.63 (m, 2 H, CH ₂ ), 2.60-2.47 (m, 3 H, CH ₂ ), 2.30-2.22 (m, 2 H, CH ₂ ), 2.04-1.96 (m, 1 H, CH ₂ ). ¹³ C-NMR (CDCl ₃ , 126.7 MHz): 5 = 152.9 (NCN), 151.6 (NCN), 66.9, 58.9, 40.9, 33.8, 33.7, 33.1 , 32.9 (CH ₂ ). Anal, calcd. for C ₁₁ H ₁₈ BrN ₃ Se: C, 37.63; H, 5.17; N, 11.97; found: C, 37.40; H, 5.18; N, 11.75. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₁ H ₁₈ N ₃ Se, m/z 272; found, m/z 272.

Compound 20. The salt was synthesized following the same procedure as for 18a using 4- mesityl-1-bromopropyl-1 ,2,4-triazolium bromide (347 mg, 1 mmol; 117), elemental tellurium (515 mg, 4 mmol) and tributyl amine (260 μL, 1.1 mmol). After reaction, the solid was removed using a sintered glass funnel and washed with methanol (3 x 5 mL ). The solvent of the filtrate was removed under reduced pressure and the solid obtained was washed with tetrahydrofurane (3 x 5 mL) to afford pure 20 as a white solid. Yield: 261 mg (0.61 mmol, 61 %). ¹ H-NMR (CDCl ₃ , 300 MHz): <5 = 8.13 (s, 1 H, NCHN), 7.02 (s, 2 H, Ar-H), 4.44 (t, 2 H, NCH ₂ ), 3.64 (t, 2 H, CH ₂ Te), 2.89 (m, 2 H, CH ₂ CW ₂ CH ₂ ), 2.36 (s, 3 H, CH ₃ ), 2.00 (s, 6 H, CH ₃ ). ¹³ C- NMR (CDCl ₃ , 126.7 MHz): <5 = 145.4 (NCN), 143.3 (NCN), 143.1, 135.5, 131.1, 128.2 (Ar-C), 53.5 (NCH ₂ ), 28.6 (CH ₂ ), 21.8 (CH ₃ ), 18.5 (CH ₃ ), 12.9 (CH ₂ ). Anal, calcd. for Ci ₄ Hi ₈ BrN ₃ Te: C, 38.58; H, 4.16; N, 9.64; found: C, 38.26; H, 4.03; N, 9.52; MS (ESI): calcd. for [M - Br] ⁺ , C ₁₄ H ₁₈ N ₃ Te, m/z 358; found, m/z 358.

Compound 21. The compound was prepared in a similar procedure with that of 17a using 4- mesityl-1-bromobutyl-1,2,4-triazolium bromide ( 403 mg, 1 mmol; 121) and tributyl amine (260 μL, 1.1 mmol). Yield: 190 mg (0.59 mmol, 59%). ¹ H-NMR (CDCl ₃ , 400 MHz): d = 8.56 (s, 1 H, NCHN), 7.05 (s, 2 H, Ar-H), 4.69 (t, ³ J _H-H = 6.0 Hz, 2 H, NCH ₂ ), 2.98 (t, ³ J _H -H = 6.0 Hz, 2 H, CH ₂ ), 2.49-2.43 (m, 2 H, CH ₂ ), 2.38-2.32 (m, 5 H, CH ₂ , CH ₃ ), 2.19 (s, 6 H, CH ₃ ). ¹³ C-NMR (CDCl ₃ , 100 MHz): <5 = 152.9 (NCN), 163.7, 143.1, 135.9, 131.0, 126.7 (Ar-C/NCN), 50.4 (NCH ₂ ), 22.0 (CH ₂ ), 21.8 (2 C, CH ₂ ), 19.2, 18.4 (CH ₃ ). Anal, calcd. for C ₁₅ H ₂₀ BrN ₃ : C, 55.91; H, 6.26; N, 13.04; found: C, 53.48; H, 6.07; N, 13.32. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₅ H ₂₀ N ₃ , m/z 242; found, m/z 242.

Compound 22. The compound was prepared in a similar procedure with that of 18a using 4- mesityl-1-bromobutyl-1,2,4-triazolium bromide (403 mg, 1 mmol; 121), elemental selenium (400 mg, 5 mmol) and tributyl amine (260 μL, 1.1 mmol). Yield: 225 mg (0.56 mmol, 56%). ¹ H- NMR (CDCl ₃ , 500 MHz): <5 = 9.44 (s, 1 H, NCHN), 7.19 (s, 2 H, Ar-H), 4.71 (t, ³ J _H - H = Hz, 2 H, NCH ₂ ), 3.43 (m, 2 H, CH ₂ ), 2.34 (s, 3 H, CH ₃ ), 2.32 (m, 2 H, CH ₂ ), 2.15 (m, 2 H, CH ₂ ), 2.02 (s, 6 H, CH ₃ ). ¹³ C-NMR (CDCI3, 126.7 MHz): <5 = 148.5 (NCN), 145.2 (NCN), 141.4, 135.0, 129.6, 128.1 (Ar-C), 54.0 (NCH ₂ ), 29.5, 29.3, 24.4 (CH ₂ ), 20.6, 17.2 (CH ₃ ). Anal, calcd. for C ₁₅ H ₂₀ BrN ₃ Se: C, 44.91; H, 5.02; N, 10.47; found: C, 43.99; H, 4.99; N, 10.09. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₅ H ₂₀ N ₃ Se, m/z 322; found, m/z 322. Compound 23. The compound was prepared in a similar procedure with that of 17a using I6 and ⁿ Bu ₃ N as a base, and the reaction was carried out at 80 °C. Pure compound obtained after washing with THF, no column chromatography required. Yield 85%. ¹ H-NMR (CD ₃ CN, 500 MHz) d = 7.76 (d, ³ J _H-H = 7.9 Hz, Ar-H), 7.71 (d, ³ J _H-H = 8.4 Hz, Ar-H), 7.59-7.51 (m, 2 H, Ar-H), 7.46-7.38 (m, 5 H, Ar-H), 5.62 (s, 2 H, NCH ₂ ), 4.45 (t, ³ J _H-H = 7.3 Hz, 2 H, CH ₂ ), 3.37 (t, ³ JH_H = 7.7 Hz, 2 H, CH ₂ ), 2.89-2.83 (m, 2 H, CH ₂ ). ¹³ C-NMR (CD ₃ CN, 126.7 MHz): d = 160.7 (NCN), 136.8, 134.3, 130.0 129.8, 129.3, 127.1, 127.0, 114.6, 114.3 (Ar-C), 50.9, 47.7, 26.1, 25.2 (CH ₂ ). MS (ESI): calcd. for [M - Br] ⁺ , C ₁₇ H ₁₇ N ₂ S, m/z 249; found, m/z 249.

Compound 24. The compound was prepared in a similar procedure with that of 18a using I6, elemental sulfur and ⁿ Bu ₃ N as a base, and the reaction was carried out at 80 °C. Pure compound obtained after washing with THF, no column chromatography required. Yield 92%. ¹ H-NMR (MeOD, 500 MHz) <5 = 7.79 (d, ³ J _H-H = 7.3 Hz, 1 H, Ar-H), 7.30 (d, ³ J _H-H = 7.3 Hz, 1 H, Ar-H), 7.58-7.51 (m, 2 H, Ar-H), 7.36-7.29 (m, 5 H, Ar-H), 5.56 (s, 2 H, NCH ₂ ), 4.51 (t, ³ J _H-H = 5.9 Hz, 2 H, NCH ₂ ), 3.61 (t, V _H-H = 5.6 Hz, 2 H, CH ₂ ), 2.59-2.54 (m, 2 H, CH ₂ ). ¹³ C- NMR (MeOD, 126.7 MHz): <5 = 151.7 (NCN), 134.5, 134.4, 132.8, 130.2, 129.9, 128.8, 127.5,

126.9, 112.9, 112.6 (Ar-C), 49.9 (NCH ₂ ), 44.6 (NCH ₂ ), 27.5, 22.3 (CH ₂ ). Anal, calcd. for C ₁₇ H ₁₇ BrN ₂ S: C, 56.51; H, 4.74; N, 7.75; S, 8.87; found: C, 55.57; H, 4.82; N, 7.77. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₇ H ₁₇ N ₂ S, m/z 281; found, m/z 281.

Compound 25. The compound was prepared in a similar procedure with that of 18a using I6, elemental selenium and ⁿ Bu ₃ N as a base, and the reaction was carried out at 80 °C. Pure compound was obtained after washing the crude product with THF (3 x 5 mL ). Yield: 86%. ¹ H- NMR (MeOD, 500 MHz): d = 7.84 (d, ³ J _H-H = 7.7 Hz, 1 H, Ar-H), 7.79 (d, ³ J _H-H = 7.9 Hz, 1 H, Ar-H), 7.61-7.55 (m, 2 H, Ar-H), 7.42-7.33 (m, 5 H, Ar-H), 5.61 (s, 2 H, NCH ₂ ), 4.56 (t, ³ J _H - _H = 5.5 Hz, 2 H, NCH ₂ ), 3.63 (t, ³ J _H-H = 5.6 Hz, 2 H, CH ₂ ), 2.71-2.67 (m, 2 H, CH ₂ ). ¹³ C-NMR (MeOD, 126.7 MHz): <5= 148.7 (NCN), 135.3, 134.5, 133.8, 130.3, 129.9, 128.7, 127.4, 126.8,

112.9, 112.7 (Ar-C), 50.6 (NCH ₂ ), 45.9 (NCH ₂ ), 24.1, 23.8 (CH ₂ ). Anal, calcd. for C ₁₇ H ₁₇ BrN ₂ Se : C, 50.02; H, 4.20; N, 6.86; found: C, 47.55; H, 4.43; N, 7.47. MS (ESI, m/z): calcd. for [M - Br] ⁺ , C ₁₇ H ₁₇ N ₂ Se, m/z 329; found, m/z 329.

Compound 26. The compound was prepared in a similar procedure with that of 18a using I6, elemental telurium and ‘BuOK as a base. Reaction was carried out at 90 °C. The compound was isolated as a white solid after purification by column chromatography using DCM/MeOH (10/1 v/v) as eluent. Yield 49%. ¹ H-NMR (MeOD, 500 MHz): d = 7.83 (d, ³ J _H-H = 7.9 Hz, 1 H, Ar-H), 7.76 (d, ³ J _H-H = 8.0 Hz, 1 H, Ar-H), 7.57-7.50 (m, 2 H, Ar-H), 7.41-7.35 (m, 3 H, Ar- H), 7.33-7.29 (m, 2 H, Ar-H), 5.58 (s, 2 H, NCH ₂ ), 4.53 (t, ³ J _H-H = 5.3 Hz, 2 H, NCH ₂ ), 3.48 (t, ³ J _H-H = 6.1 Hz, 2 H, CH ₂ ), 2.79-2.74 (m, 2 H, CH ₂ ). ¹³ C-NMR (MeOD, 126.7 MHz): d = 138.8 (NCN), 136.4, 135.1, 134.7, 130.3, 129.9, 128.7, 126.9, 126.5, 112.9, 112.6 (Ar-C), 51.9 (NCH ₂ ), 48.1 (NCH ₂ ), 26.9, 6.8 (CH ₂ ). Anal, calcd. for C ₁₇ H ₁₇ BrN ₂ Te: C, 44.70; H, 3.75; N, 6.13; found: C, 43.99; H, 3.65; N, 6.61. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₇ H ₁₇ N ₂ Te, Te m/z 379; found, m/z 379.

Compound 27. The salt was synthesized in a similar procedure with that of 18a using 1-benzyl- 3-(3-bromopropyl)-imidazolium bromide (I27), elemental sulfur and ⁿ Bu ₃ N as a base, and reaction was carried out at 80 °C. Yield: 60%. ¹ H-NMR (CDCI ₃ , 400 MHz): <5 = 8.52 (d, ³ J _H-H = 2.2 Hz, 1 H, NCH), 7.09 (d, ³ J _H-H = 2.2 Hz, 1 H, NCH), 7.02 (s, 2 H, Ar-H), 4.93 (t, ³ J _H-H = 5.5 Hz, 2 H, NCH ₂ ), 3.56 (t, ³ J _H-H = 5.5 Hz, 2 H, CH ₂ ), 2.58-2.52 (m, 2 H, CH ₂ ), 2.35 (s, 3 H, CH ₃ ), 2.03 (m, 6 H, CH ₃ ). ¹³ C-NMR (CDCI ₃ , 100 MHz): d = 142.6 (NCN), 142.5, 135.9, 130.7, 129.3, 126.5, 121.8 (NCH/ Ar-C), 47.9 (NCH ₂ ), 26.7, 22.7 (CH ₂ ), 21.8, 18.4 (CH ₃ ). Anal, calcd. for C ₁₅ H ₁₉ BrN ₂ : C, 53.10; H, 5.64; N, 8.26; found: C, 52.41 ; H, 5.50; N, 9.27; S, 9.27. MS (ESI, m/z): calcd. for [M - Br] ⁺ , C ₁₅ H ₁₉ N ₂ , m/z 259; found, m/z 259.

Compound 28. The salt was synthesized in a similar procedure with that of 18a using 1-benzyl- 3-(3-bromopropyl)imidazolium bromide (I27), elemental selenium and ⁿ Bu ₃ N as a base, and reaction was carried out at 80 °C. Yield 70%. ¹ H-NMR (CD ₃ CN, 500 MHz): d = 7.71 (br. s, 1 H, CHCH), 7.44 (br. s, 1 H, CHCH), 7.13 (s, 2 H, Ar-H), 4.33 (t, ³ J _H-H = 5.6 Hz, 2 H, NCH ₂ ), 3.42 (t, ³ J _H-H = 5.73 Hz, 2 H, CH ₂ ), 2.49 (m, 2 H, CH ₂ ), 2.35 (s, 3 H, CH ₃ ), 2.00 (s, 6 H, CH ₃ ). ¹³ C-NMR (CD ₃ CN, 127.6 MHz): <5= 142.8 (NCH), 136.5 (NCH), 130.8 (2 C, Ar-C), 130.7 (NC), 126.4 (Ar-C), 123.6 (Ar-C), 48.9 (NCH ₂ ), 24.1, 22.8, 21.2, 17.5 (CH ₂ & CH ₃ ). Anal, calcd. for C ₁₅ H ₁₉ BrN ₂ Se: C, 46.65; H, 4.96; N, 7.25; found: C, 44.37; H, 4.73; N, 7.72. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₅ H ₁₉ N ₂ S e, m/z 307; found, m/z 307.

Compound 29. The compound was prepared in a similar procedure with that of 18a using 3- (3-bromopropyl)benzothiazolium bromide (I29), elemental sulfur and T3uOK as a base. Reaction was carried out at 90 °C. The compound was isolated as a white solid after purification by column chromatography using DCM/MeOH (10/1 v/v) as eluent. Yield 71%. ¹ H- NMR (MeOD, 500 MHz): d = 8.18 (d, ³ J _H-H = 8.2 Hz, 1 H, Ar-H), 8.06 (d, ³ J _H-H = 8.4 Hz, 1 H, Ar-H), 7.82 (t, ³ J _H-H = 8.4 Hz, 1 H, Ar-H), 7.73 (t, ³ J _H-H = 7.8 Hz, 1 H, Ar-H), 4.69 (t, ³ J _H-H = 6.0 Hz, 2 H, NCH ₂ ), 3.65 (t, ³ J _H-H = 5.8 Hz, 2 H, CH ₂ ), 2.69-2.65 (m, 2 H, CH ₂ ). ¹³ C-NMR (MeOD, 500 MHz): <5 = 177.0 (NCS), 143.4, 130.2, 129.2, 128.5, 124.5, 115.8 (Ar-C), 48.2 (NCH ₂ ), 28.6, 21.5 (CH ₂ ). Anal, calcd. for Ci ₀ Hi ₀ BrNS ₂ : C, 41.67; H, 3.50; N, 4.86; S, 22.25; found: C, 38.80; H, 3.44; N, 5.28; S, 19.77. MS (ESI): calcd. for [M - Br] ⁺ , C ₁₀ H ₁₀ BrNS ₂ , m/z

208; found, m/z 208. Compound 30. The compound was prepared in a similar procedure with that of 18a using 3- (3-bromopropyl)benzothiazolium bromide (I29), elemental selenium and T3uOK as a base. Reaction was carried out at 90 °C. The compound was isolated as a white solid after purification by column chromatography using DCM/MeOH (10/1 v/v) as eluent. Yield: 49%. ¹ H-NMR (MeOD, 500 MHz): δ = 8.19 (d, ³ J _H-H = 8.1 Hz, 1 H, Ar-H), 8.11 (d, ³ J _H-H = 8.4 Hz, 1 H, Ar-H), 7.83-7.79 (m, 1 H, Ar-H), 7.73-7.69 (m, 1 H, Ar-H), 4.72 (t, ³ J _H-H = 5.5 Hz, 2 H, NCH ₂ ), 3.67 (t, ³ J _H-H = 5.7 Hz, 2 H, CH ₂ ), 2.79-2.75 (m, 2 H, CH ₂ ). ¹³ C-NMR (MeOD, 126.7 MHz): d = 173.5 (NCS), 144.3, 130.5, 130.0, 128.9, 124.4, 115.9 (Ar-C), 49.8 (NCH ₂ ), 24.8, 23.7 (CH ₂ ). MS (ESI, m/z): calcd. for [M-Br] ⁺ , C ₁₀ H ₁₀ NSSe, m/z 255; found, m/z 255. Example 7: Oxidation of compound 14

The neutral heterocycles 14-16 are promising medicinal compounds, and hypocholesterolemic activity has been revealed in vivo for compound 14. Moreover, further oxidation to afford sulfoxide and sulfone derivatives as potentially bioactive compounds is possible. Given this, compound 14 was chosen as a representative for a preliminary screening of oxidants (e.g. Phl(OAc) ₂ , H ₂ O ₂ , oxone).

Procedure for the synthesis of sulfoxide 32 and sulfone 33 Scheme 11. Oxidation of 14 to sulfoxide (32) and sulfone (33).

Compound 14 (50 mg, 0.26 mmol) and oxone (120 mg, 0.39 mmol) were suspended in H ₂ O (1 ml.) and stirred overnight at 60 °C. The resulting pink suspension was extracted with CH ₂ Cl ₂ , and the organic phase was combined and subjected to column chromatography (SiO ₂ , hexane/EA/CH ₂ Cl ₂ : 1/2/1, then CH ₂ Cl ₂ /MeOH: 25/1). Compound 32 was collected as the lower spot (Rf: 0.05, hexane/EA/CH ₂ CI ₂ : 1/2/1 ,) and isolated as a white solid (31%). Compound 33 was collected as the upper spot (Rf: 0.33, hexane/EA/CH ₂ Cl ₂ : 1/2/1 ,) and isolated as a white solid (24%).

Compound 32. Yield: 17 mg, 0.08 mmol, 31%. ¹ H NMR (400 MHz, CDCI ₃ ): 57.87 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.44-7.37 (m, 3 H, Ar-H), 4.54-4.48 (m, 1 H, NCH ₂ ), 4.21-4.14 (m, 1 H, NCH ₂ ), 3.50-3.46 (m, 1 H, SCH ₂ ), 3.27-3.15 (m, 2 H, SCH ₂ and CH ₂ ), 2.47-2.40 (m, 1 H, CH ₂ ). ¹³ C{ ¹ H} NMR (126 MHz, CDCl ₃ ): d 148.8 (NCN), 142.7, 135.0, 126.1 , 124.8, 122.2, 110.7 (Ar-C), 46.1 , 43.8, 14.2 (CH ₂ ). Anal. Calcd. forC ₁₀ H ₁₀ N ₂ OS: C, 58.23; H, 4.89; N, 13.58. Found: C, 58.44; H, 5.08; N, 13.73. HRMS (ESI) m/z calcd. forC ₁₀ H ₁₀ N ₂ OS [M + H] ⁺ 207.0587; found, 207.0588.

Compound 33. Yield: 14 mg, 0.06 mmol, 24%. ¹ H NMR (500 MHz, CD ₃ CN): d 7.82 (d, ³ J(H,H) = 8 Hz, 1H, Ar-H), 7.52 (d, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.48 (t, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 7.41 (t, ³ J(H,H) = 8 Hz, 1 H, Ar-H), 4.32 (t, ³ J(H,H) = 6 Hz, 2H, NCH ₂ ), 3.67-3.64 (m, 2H, SCH ₂ ), 2.77-2.73 (m, 2H, CH ₂ ). ¹³ C{ ¹ H} NMR (125 MHz, CD ₃ CN): d 149.4 (NCN), 142.1, 135.0, 126.3, 125.0, 121.9, 112.4 (Ar-C), 51.8, 43.9, 22.6 (CH ₂ ). Anal. Calcd. for C ₁₀ H ₁₀ N ₂ O ₂ S: C, 54.04; H, 4.54; N, 12.60. Found: C, 53.85; H, 4.72; N, 12.46. HRMS (ESI) m/z calcd. for C ₁₀ H ₁₀ N ₂ O ₂ S [M + H] ⁺ 223.0536; found, 223.0532.

Discussion

The study reveals the necessity of oxone as a strong oxidizer, which affords both two compounds 32 and 33 in one-pot that were separated by column chromatography (Scheme 11). This results indicates a rather weak nucleophilic character of the new heterocycles.

Upon oxidation, compounds 32 and 33 become less soluble in common organic solvents such as ether and CHCI ₃ . Compounds 14 and 33 show similar NMR resonances, in which three signals are observed for the methylene protons. However, those of the sulfoxide compound 32 become diastereotopic and give two sets of signals for each CH ₂ (see characterization results above).

Conclusion

We have reported a new and simple one-pot approach to cationic thiazolino-azolium salts and neutral azole-thiazolines from N-bromoalkylazolium salts. Advantages of this method include (i) easily available and cheap starting materials; (ii) simple reaction and work-up procedures with high yields; and (iii) high modularity and versatility via easy variations of backbone, linker and substituents. Extension of this strategy to a greater library of N-fused heterocycles and exploration of their chemistry is underway. Moreover, the suitability of the cationic heterocycles as precursors to sulfur-functionalized NHC complexes will be explored.