Thiete Dioxides as Templates Towards Twisted Scaffolds and Macrocyclic Structures

Abstract Thiete dioxide units have been employed as a template for further functionalization through C−H activation strategies. Using simple thiete dioxide building blocks, a new library of axially chiral molecules has been synthesized that owe their stability to electrostatic interactions in the solid state. Similar starting materials were further engaged in the formation of cyclic trimeric structures, opening the pathway to unprecedented macrocyclic ring systems.


Introduction
Thiete dioxides possess unique electronic and structuralp roperties. [1] Althoughn aturalp roducts containing thiete cores were not to be found in the literature,t hey constitute an interesting entry point to their saturated analogs, thietanes, which have found applicationsi nd rug discoveryo rd emonstrated their interesting properties in life-science as pesticide or sweetener. [2] In the course of our program dedicated to the development of efficient routest owards unsaturated four-membered rings, we recently put together simple strategies for the synthesis and functionalization of cyclobutenes, [3] azetines [4] and2 Hthiete dioxides, [5] as well as their involvement in accessing sophisticated fused ring systems. [6] Concerning 2H-thieted ioxides, two sequences were developed. While the first one relies on an a-lithiation/transmetalation/Negishi cross-coupling sequence, the second is based on CÀHa ctivationstrategy and allows for ab road and tolerant functionalization of the unsaturated S-containingf our-membered ring scaffold.
Given that such structures constitute au nique entry in the repertoire of strained heterocycles,w es et out to take the next step in their architectural diversification. We describe herein the studyo fp alladium-catalyzed CÀHf unctionalization of 3substituted thieted ioxides towards the formationo fc hiral disubstituted thiete dioxides and thiete dioxide-based macrocy-cles (Scheme 1). Axial chiralityi so fg reat importancei nm any areas of chemistry and is not limited to the synthesis of novel catalysts [7] and atropisomers [8] butp lays an important role in drug design. [9] Besidet hat, thiete dioxide-based macrocycles can be interesting analogs to the knownc ompound class, namely spherands,w hich weref irst reported by Cram in 1979. [10] They can be classifieda sm acrocyclic ligandsw ith limited conformational flexibility. With ap reorganizationa nd an electron-pair-lined cavity,t hey are strong complexationr eceptors for ions, such as lithium,s odium or potassium. [11] Indeed, the binding constant for lithium ions is one of the strongest reportedt od ate. [12,13] With this in mind, the preparationo ft hiete dioxideb ased macrocyclic structuresw as envisioned. Therefore, 3-substitutedt hiete dioxide units bearing ab romide at the meta position of the aryl substituent were utilized (Scheme 1).

Results and Discussion
The project wasi nitiated by synthesizingar ange of 3-substituted thiete dioxide building blocks.S tarting from commercially available3 -thietanone, the addition of an organomagnesium or an organolithiumf urnished the corresponding tertiarya lcohols after hydrolysis (Scheme 2). The crude product was subsequently oxidized with mCPBA to give thietane 1.D esired building blocks 2a-t were obtained upon addition of mesyl chloride andt rimethylamine, triggering a b-elimination to generate the double bond. For simple aromatic systems( phenyl, naphthyl, anthryl), we have witnessed ag eneral decrease in efficiency with increasing sterical hindrance (from 78 %f or 2a to 25 % for 2c). However, the procedure provedt ob eq uite versatile, allowing for the introduction of av ariety of substituents, including electron deficient groups (p-fluorophenyl, m-trifluomethylphenyl or 8-quinolinyl) ande lectron richs ubstituents (p-, m-o ro-methoxyphenyl).Abroad range of functionalized compounds (2a-u)w as isolated in moderate to good yields over three synthetic steps (22 to 78 %).
In the course of our study on the functionalization of thiete dioxides through CÀHa ctivation, we synthesized ar ange of bis-arylated structuress uch as 3a (70 %), employing catalytic amountso fP d(OAc) 2 in the presenceo fp ivalic acid, tricyclohexyl phosphine and potassium carbonate (Scheme 3). In our previousr eport, we showed that such catalytic system preferentiallyf ollows aB IES (base-assisted intramolecular electrophilic substitution) mechanism.W ith two naphthyl groups at positions 3a nd 4, four different conformers of 3a (out;out, out;in, in;out and in;in)c an be anticipated. Although steric factors could have ruled out conformers II, III and IV,acrystal structure of compound 3a (Scheme 3) showed that conformer III (in;in)i se xclusively observedi nt he solid state. [14] In 3a(III), two s-bonds are twisted, providing the molecule with ah elical shape. In addition to steric factors, it has been demonstrated that electronic effects can playadeterminant role in the geometrical arrangemento fe lectron-poor strained ring systems, as in the present case. [15] The observation of such thiete dioxide-basedd ouble axial chirality in the solid state might providet he opportunity towards the development of novel chiral scaffolds. However,d espite having evidence for chirality in the crystal structure of 3a(III), we questioned the configurational stability of the structures in solution, as no evidence for enantiomer separation could be demonstrated under various chromatographic conditions, probablyd ue to a low rotation barrier.W eb ecamei nterested in studying the influence of substituents and electronic effects on both aryl parts of the structure.
We first investigated the influence of different aromatic groups on the axial chirality.C ompounds 3b and 3c were synthesized from 2b and 2c,r espectively and 1-bromoisoquinoline in 43-70 %y ield. 9-Bromoanthracene was also used as a cross-coupling partner, giving 3d in 62 %, that also showed axial chirality in the solid state.
However,t he rigidity of the two aryl groups resultsi ni nterplanar angles( f)o f6 3.18 and 80.48 in the structureso f3a and 3d,r espectively,w hich does not allow them for adapting to one another [16] -separation of enantiomers in solution remained unsuccessful. As Wittig already observed when synthesizing phenanthrene derivatives, [17] electrostatic interactions play ad eterminant role in the stabilization of axial chirality.W e envisioned to modulate the nature of the aryl substituents to increaset heir affinity for one another.W et herefore designed new structures to evaluate the impact of electron-donor and electron-acceptor moieties, as well as their bulkiness,o nt he stabilization of the stereointegrity.
In order to increase potential interactions, somef lexibility was added to the cross-coupling partner in such way that the molecule couldg ain stabilityb yd ecreasing the interplanar angle between the aromatic moieties at positions 2a nd 3.
Moreover,g iven the initial polarization of the thiete dioxide moiety, [6c] electron deficient coupling partners were chosen to be introduceda tp osition2.W ith 3-naphthylthiete dioxide 2b as starting material, molecules 4a and 4b were synthesized As evidenced by X-ray measurements, thesec hains seem to fold on top of the naphthyl group.The implementation of flexibility through ak eto group or a s-bond betweent he phenyl and the aryl moiety at position 2a llowedf or reaching interplanar angles of 15.48 (4a)a nd 14.18 (4b)b etween the naphthyl at position3 and the phenylg roup. The bulkiness of the aryl at position 3was furtherincreasedbyimplementation of amesityl group (from 2e). Similarly,f olding of the side phenylpyridyl chain (electron poor) onto the mesityl moiety was observed in the solid state (4d), showing however aw ider interplanar angle of 36.88.S ame observations were made when mesityl was replaced by electron-richer aromatics such as 3,4,5-trimethoxyphenyl or 4-methoxyphenyl in structures 4f and 4g,s ynthesized from thiete dioxides 2j and 2f,r espectively.I ti s worth noting that methoxy-substituted aryls at position3a re in the same plane as the thiete core (08 dihedral angle), inducing aw ider interplanar angle (f 4 f = 548). Next, 3-([1,1'-biphenyl]-2-yl)-thiete dioxide 2d wasu sed as starting material in order to introduce flexibility at position 3.
CÀHf unctionalization was performed with neutral, electronrich ande lectron-poora ryl and heteroaryl coupling partners, giving products 5a-f in moderate to good yields, up to 93 %. Surprisingly,t he "out"c onformation of the biphenyl was favored in all cases,a sa ttested by the crystal structures of 5a and 5h.T he absence of folding was also witnessed when electron-enriched biaryl (p-MeO) was introduced at position3 (5g, 60 %), in the presence of an electron-poor phenyl( p-NO 2 ). The presenceo falarger pyrenyl moiety at position 4d id not positively influence intramolecular interactions (5h). However,t he introduction of an electron-donating group on the naphthyl moiety (2-methoxynaphthalen-1-yl) tremendously decreased the interplanar angle when having flexible electron-deficient biaryl moieties at position 2, probably due to stronger non-covalent interactions. Compounds 6a and 6b were synthesized employing 4-(2-bromophenyl)pyridine and 2-bromo-3',5'-dinitro-1,1'-biphenyl, respectively,a nd displayedt orsion angles of 5.88 and 8.08.I nterestingly,s plitting in 13 CNMR signals of 6a was observed, [13] pointing out the highers tructural constraint of the molecule. Although examples 5a-h did not show any folding in the solid state, the presence of an additional flexible chain at position 2a llowed for both biaryl to fold onto one another.S tartingf rom 3-substitutedt hiete dioxides 2d and 2i, tetraarylated scaffolds 6c and 6d were generated in 57 to 88 %y ield using 4-(2-bromophenyl)pyridine. X-ray measurements revealed that the flexibility given to both chains at positions 3a nd 2w as profitable to the system,a llowing fora better adaptation of the different groups with their respective counterpart. For instance, the electron-rich phenyl moiety C in compound 6c was found to be placed in opposition to the phenylg roup B with at orsion angle of 11.18,a nd the electronpoor pyridyl group A opposest he phenyl group D with at orsion angle of 16.78.S imilar observations were made for compound 6d,a lthough aw ider angle of 23.18 wasm easured between aromatic rings B and C. Unfortunately,d espite having optimized the electrostatic interactions, none of the above-mentioned examples showeda ny stable chirality in solution.
Tuning the electronic properties of the substituents as well as their bulkiness did not allow for two enantiomerst ob eobserved, even at low temperature, pointing out the low rotation barrieroft hese systems.
The variationso fb oth substituents andc oupling partners allowed for the synthesiso fawide range of sophisticated structures with specific geometries. To push the diversification further,w ee nvisioned to employ thiete dioxide units that could act as the coupling partner, as at emplate in the CÀHf unctionalizations tep. For this purpose, mono-arylated thiete dioxides possessing ab romide at the meta positiono ft he aryl moiety (2l, n, p-u)w ere engaged in the presence of the above-mentioned catalytic system.
Although different products of successive couplings can be expected (linear oligomers or macrocycles), trimericm acrocycles were observed as the major components of the reaction (Scheme 4). Given the specific geometry of the startingm aterial, it was postulated that the entropic factor plays ad eterminant role in the formation of the trimers, disfavoring larger sizes of cyclic structures (although they were observeda ss ide products in mass spectroscopy in certain cases). Even though full conversion of starting materials 2 was observed after 16 h, 7a-h were obtained in low to moderate yields (15 to 45 %), which we attributedt ot he very low solubility of the products in common solvents. Best yields (42 to 45 %) were obtained for m-methoxy and m-fluoro-phenyl derivatives( 7e and 7d)a nd the reaction provedt ot olerate bulkiers ubstituents like tertbutyl and phenylgroupsatthe meta positionwith reduced isolated yields (7c and 7f,g,1 5t o19 %). Considering procedures for the synthesis of related macrocyclic spherands, the yields between 20 and 45 %a re quite good. Moreover,agram scale procedure of macrocycle 7e was successful conducted in similar yield of 41 %. Interestingly,w ew ere able to synthesize larger trimericc yclic "naphthyl-thiete dioxide-based macrocycle" 7h,f or which the solubility problems in classical solvents did not allow for its isolation in more than 20 %y ield. Crystal structures of 7a and 7e confirmt he cyclic structures,c onsisting of three thiete dioxide units. Moreover,d ue to non-aromaticity of the cyclic system and sterical repulsion an on-planar ring system can be observed in the X-ray structures.
As an ext step, we attempted to form am acrocycle showing more structural similarityt ot he spherand reported by Cram, which bears methoxy-groups inside the cavity (Scheme 1). [8] For this purpose, 2o was chosen as the buildingunit. The reaction resulted in the trimeric structure 7i,g iving am odest yield of 15 %( Scheme 5). Although the compound was identified in mass spectrometry, 1 Ha nd 13 CNMR remained inconclusivea nd no crystal structure could be obtained. After further investigation of the reaction, we observed that in certainc ases at etrameric structure wasf ormed. When employing 2r as the thiete dioxide-unit, we were able to not only isolates tructure 7g,but also isolate the tetrameric structure 8a in av ery modesty ield of 6%.D espite the bad solubility of the compound, we were able to recorda 1 Hs pectrum, showingw idely broadened signals compared to the spectrum of the correspondingt rimer 7g.T his phenomenon can be attributedt ot he constricted flexibility of such system, and conducting NMRm easurements at highert emperature allowed us to acquire sharper signals. Furthermore, we employed the p-bromo-phenyl thiete dioxide 2u in the attemptt of orm the tetramer 8b.U nfortunately,n o reactionwas observed.

Conclusions
In this work, we at first expanded our scope of 3-substituted thiete dioxide-based building blocks, forming new compounds containing bulkiera romatic substituents, as well as new functional groups. We were then able to functionalize these, following as imple CÀH-activation strategy.T hereby,w ec reated a new libraryo f2 ,3-disubstituted thiete dioxides, showinga xial chiralityi nt he solid state. We then showed that the thiete dioxide unit can also act as the coupling partneri tself, allowing for the synthesis of novel macrocyclic compounds. In conclusion, our results show that the thiete dioxide moiety can be used as av ery versatile platform for molecular design,w hich makes it an attractive structure for furtherinvestigation.

Experimental Section
Generalp rocedure A: For the synthesis of thiete dioxides 2a-u: Af lask was charged with thietan-3-one (10.0 mmol, 1.0 equiv) and THF (0.5 m)w as added. The reaction mixture was cooled to À78 8C and as olution of organolithium reagent (1.30 equiv) was added dropwise. Alternatively,t he reaction mixture was cooled to À30 8C and as olution of organomagnesium reagent (1.30 equiv) was added dropwise. After stirring for 60 min the mixture was brought to ambient temperature and quenched with as olution of saturated aqueous NH 4 Cl. The aqueous phase was extracted with dichloromethane (3 50 mL) and washed with asolution of saturated aqueous NaCl (1 50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue, containing the thietanol, was dissolved in dichloromethane (50 mL), cooled to 0 8Ca nd mCPBA (20.0 mmol, 2.0 equiv,7 7%) was added portion wise. After TLC showed full conversion of the thietanol (approx. 10 min) water was added. The aqueous phase was extracted with dichloromethane (3 50 mL) and washed with asolution of saturated aqueous NaCl (1 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue, containing the thietanol dioxide 1, was dissolved in dichloromethane (50 mL) and triethylamine (30 mmol, 3.0 equiv) was added. Mesyl chloride (30 mmol, 3.0 equiv) was subsequently added dropwise and the mixture was stirred until TLC indicated full conversion of the starting thietanol dioxide 1 (approx. 30 min) water was added. The aqueous phase was extracted with dichloromethane (3 50 mL) and washed with asolution of saturated aqueous NaCl (1 50 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude thiete dioxides 2a-u were purified by flash column chromatography with appropriate solvent mixtures.