+

WO2016039691A1 - Catalysts for making chiral heterocyclic sulfoxides - Google Patents

Catalysts for making chiral heterocyclic sulfoxides Download PDF

Info

Publication number
WO2016039691A1
WO2016039691A1 PCT/SG2015/050309 SG2015050309W WO2016039691A1 WO 2016039691 A1 WO2016039691 A1 WO 2016039691A1 SG 2015050309 W SG2015050309 W SG 2015050309W WO 2016039691 A1 WO2016039691 A1 WO 2016039691A1
Authority
WO
WIPO (PCT)
Prior art keywords
mhz
nmr
cdci
compound
yield
Prior art date
Application number
PCT/SG2015/050309
Other languages
French (fr)
Inventor
Choon Hong Tan
Lili ZONG
Original Assignee
Nanyang Technological University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanyang Technological University filed Critical Nanyang Technological University
Publication of WO2016039691A1 publication Critical patent/WO2016039691A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Optically active sulfoxides are extensively used as chiral auxiliaries, chiral ligands for meta! complexes and organocatalysts. This unique moiety is also found in several marketed drugs such as Esomeprazole (proton pump inhibitor), Armodafini! (eugeroic) and Sulindac (anti- inflammation).
  • Esomeprazole proton pump inhibitor
  • Armodafini! eugeroic
  • Sulindac anti- inflammation
  • A represents an anionic counterion
  • R represents a fragment of formula (II):
  • each X independently represents Ci, Br or I.
  • each X is the same and may represent CI, Br or I.
  • all X groups may represent I.
  • the compound of formula (I) may be chrial.
  • the compound of formula (I) may be a compound of formula (la) or formula (lb):
  • A may be an anionic counterion selected from the group consisting of CI “ , Br " , ⁇ and F " .
  • the compound of formula (!) may be selected from:
  • a use of a compound of formula (I) as described hereinbefore as a catalyst for a chemical reaction may result in one or more enantioenriched products, in particular embodiments of the invention, the chemical reaction is the preparation of sulfoxides (e.g. enantioenriched sulfoxides).
  • a method for preparing an enantoenriched sulfoxide comprising, reacting a compound of formula (III): with a compound of formula (IV):
  • Ri represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted alkyl group;
  • R 2 represents and electron withdrawing group
  • R 3 represents a substituted or unsubstituted alkyl group.
  • the solvent may comprise an ether (e.g. cyclopentyl methyl ether and/or diethyl ether). In still further embodiments, the solvent may further comprise water. In still further embodiments of the invention, the reaction may be conducted at a temperature of from -50°C to -80°C (e.g. from -60°C to -70°C). A catalytic amount of a compound of formula (I) may be from 0.0001 mol% to 20 mol%, such as from 0.001 to 2 mol%, e.g. 1 mol%.
  • the base may be a metal hydroxide, such as cesium hydroxide.
  • R 2 may represent -C(0) 2 Me, -C(0) 2 Et, -0(0) 2 3 ⁇ 4 ⁇ , -C(0) 2 Ph, S0 2 Ph and -CN.
  • Figure 1 depicts drugs containing thiophene moieties.
  • Figure 3 depicts the general procedure for the synthesis of chiral pentanidium salts (using the pentanidium salt 1c as an example).
  • Figure 4 depicts a working model hypothesis for the sulfenate anion intermediate.
  • Figure 5 depicts the single crystal structure of the (R)-form of compound 6q. Description
  • brominated pentanidium 1 c provided sulfoxides with marginally better enantioselectivities.
  • sulfoxide 3a can be formed when halogenated pentanidiums were used as catalysts with benzyl chloride (path a). These results indicate the ability of halogenated pentanidiums to activate both the electrophile and the sulfenate anion nucleophile.
  • each X independently represents CI, Br or I.
  • anionic counterion may refer to any anionic species that can form an ion pair with the positive charge on one of the nitrogen atoms of the compound of formula (I).
  • the anionic counter ion may be the anion of a carboxylic acid or it may be an anionic halogen ion (e.g. Br " , ⁇ , F " or, more particularly, CI " ).
  • the substituent X may be the different or, more particularly, the same. For example, when each X is the same, X may represent one of CI, Br or, more particularly, i.
  • the compounds of the current invention may be particularly useful as catalysts in enentioselective reactions.
  • the compound of formula (I) may be chiral.
  • the compound of formula (1) may be a compound of formula (la) or formula (lb):
  • the compound of formula (I) may be selected from:
  • the compound of formula (I) may be used as a catalysts for a chemical reaction.
  • a compound of formula (I) as described hereinbefore as a catalyst for a chemical reaction.
  • the chemical reaction may result in one or more enantioenriched products.
  • the chemical reaction is the preparation of sulfoxides (e.g. enantioenriched sulfoxides).
  • the term "enantioenriched” is intended to refer to a product of a chemical reaction involving the compound of formula (I), wherein said product has an enantiomeric ratio that is greater than 50 : 50 but less than 100 : 0.
  • the enantioenriched compound is not racemic and may, for example, have an enantiomeric excess (ee) of from 50% to 99.99% ee.
  • a method for preparing an enantoenriched sulfoxide comprising, reacting a compound of formula (III): with a compound of formula (IV): R 3 -X 1 (IV)
  • a catalytic amount e.g. from 0.0001 mol% to 20 mol%, such as from 0.001 to 2 mol%, i.e. 1 mol% of a compound of formula (I) as defined in any one of Claims 4 to 6, a base and a solvent, to provide the enantioenriched sulfoxide, wherein:
  • R 1 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted alky! group;
  • R 2 represents and electron withdrawing group
  • R 3 represents a substituted or unsubstituted alkyl group.
  • aryl when used herein includes C 6 .1 (such as C 6 .io) 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 naphthyl or, more particularly, phenyl.
  • alkyl refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl)hydrocarbyl radical.
  • alkyl refers to an acyclic group, it is preferably C O alkyl and, more preferably, C -6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), prop-1-eneyl, 2- methylisoprop-1-eneyl, butyl (e.g. branched or unbranched butyl), but-2-ynyl, pentyl ormethyl).
  • alkyl is a cyclic group (which may be where the group “cycloalkyl” is specified), it is preferably C3. 1 2 cycloaikyl and, more preferably, C 5 .io (e.g. C 5-7 ) cycloalkyl.
  • 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 4 (e.g. 10 ⁇ members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic.
  • 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, benzimidazoiyi, 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, benzomorpho!inyl, benzoselenadiazoiyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furany
  • 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.
  • heteroaryl groups include pyridyl, pyrrolyl, quinoiinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinoiinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl.
  • heteroaryl groups include monocylic heteroaryl groups (e.g. furan, and thiophene).
  • a "substituted" group refers to a group (e.g. an aryl, a heteroaryl or an alkyl group as defined hereinbefore) substituted with one or more substituents selected from halogen, an aikyl group, phenyl (which may be unsubstituted or substituted by halogen, -OAIky!, -COAIkyl, -C ⁇ 0) 2 Alkyl, -S0 2 alkyl and -CN), naphthyl (which may be unsubstituted or substituted by -OAIkyl, -COAIkyl, -C(0) 2 Alkyl, -S0 2 alkyl and -CN), -OAIkyl, -COAIkyl, -C(0) 2 Alkyl, -S0 2 alkyl and -CN.
  • the solvent may comprise an ether (e.g. cyclopentyl methyl ether and/or diethyl ether). In still further embodiments, the solvent may further comprise water.
  • the reaction may be conducted at a temperature of from -50°C to -80°C ⁇ e.g. from -60°C to -70°C).
  • the base may be a metal hydroxide, such as cesium hydroxide.
  • electron withdrawing group will be understood to mean a moiety that enables the deprotonation of the carbon atom alpha- to said electronwithdrawing group. Examples of electron withdrawing groups that may be mentioned herein includes -C(0) 2 e, -C(0) 2 Et, -C(0)2 l Bu, -C(0) 2 Ph, S0 2 Ph and -CN, that is R 2 may be any of these groups.
  • Optically active sulfoxides have extensive applications as chiral ligands, chiral organocatalyst, synthetic intermediates and bioactive drugs. The importance and the unique property of sulfoxide compounds promote the developing the synthetic approaches to them.
  • the classical Andersen method and the Kagan-Modena method. Many modification based on these two approaches also have been developed.
  • the development of catalytic and enantioselective methodologies with broad substrate scope and using non-metallic chiral catalysts is still highly desirable, which has been developed herein.
  • the chiral heterocyclic sulfoxides made using the compound of formula (1) could potentially be used as chiral organocatalyst, chiral ligand for metal complexes, biologically active molecules or drugs.
  • LRMS Low resolution mass spectra
  • HRMS High resolution mass spectra
  • Enantiomeric excess values were determined by HPLC analysis on Shimadzu LC-20AT and LC-2010CHT HPLC workstations.
  • THF THF were distilled over sodium/benzophenone under N z atmosphere.
  • Toluene, Acetonitrile and Dichloromethane were distilled over CaH 2 under N 2 atmosphere.
  • the mercaptans were purchased from commercial suppliers or synthesized according to the literature procedures and used directly without further purification. Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated. Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. All compounds synthesized were stored in a -30 °C freezer.
  • Example 1 Representative procedure for the syntheses of chirai pentanidium salts (taking the pentanidium salt 1c as an example):
  • Step 1 To a solution of chirai diamine A (1.23 g, 5.8 mmol, 1.0 equiv.) and K 2 C0 3 (1.77 g, 12.8 mmol, 2.2 equiv.) in MeCN (15 mL), was added a solution of 2-bromo-3,5-di-tert- butylbenzyl bromide (4.30 g, 11.9 mmol, 2.05 equiv.) in MeCN (15 mL) by using a syringe pump during 1 h, and then the reaction mixture was stirred for 24 h at room temperature (monitored by TLC).
  • Step 2 A 50 ml flask was charged with 1.0 mL CH 2 CI 2 , compound B (522 mg, 0.67 mmol, 1.0 equiv.), and K 2 C0 3 (205 mg, 1 ,48 mmol, 2.2 equiv.) in 1.5 mL H 2 0. The resulting mixture was stirred vigorously at 0 °C, followed by the dropwise addition of an anhydrous CH 2 CI 2 solution of triphosgene (1.0 M, 67 mg, 0.22 mmol, 0.33 equiv.). After the addition, the mixture was warmed to room temperature and further stirred for 2 h to complete the reaction. The reaction mixture was then extracted with CH 2 CI 2 (5 mL ⁇ 3).
  • Step 3 To a solution of compound C (515 mg, 0.64 mmol, 1.0 equiv.) in 3.0 mL o-xylene was added Lawesson's reagent (518 mg, 1.28 mmol, 2.0 equiv.) under nitrogen atmosphere. Then the whole solution was heated to 145 °C for 24 h and cooled to room temperature. Upon the completion of compound C on TLC, the whole solution was directly loaded on a column. Firstly, all the o-xylene was allowed to drain by gravity and then hexane/ethyl acetate ( 00:1- 20:1 ) was used to flush out compound D as a pale-yellow foam, 508 mg, 96% yield.
  • Lawesson's reagent 518 mg, 1.28 mmol, 2.0 equiv.
  • Step 4 A 100 mL RBF was charged with a solution of D (508 mg, 0.62mmol, 1.0 equiv.) in toluene (3 mL) with a condenser under N 2 atmosphere.
  • (COCI) 2 (0.43 mL, 4.97 mmol, 8.0 equiv.) was added via syringe in one portion. The mixture was refluxed overnight until D was completely reacted. Toluene was removed under reduced pressure and solid imidazoline salt was obtained for the next step without any purification.
  • Imidazoline salt is air and moisture sensitive, which should be stored under nitrogen atmosphere or vacuum.
  • Step 5 To a solution of B (775 mg, 1 mmol, 1.0 equiv.) in dry MeCN (5 mL) under nitrogen atmosphere was added BrCN (106 mg, 1 mmol, 1.0 equiv.). The whole solution was heated to reflux for 12 h and cool to room temperature. Then solvent was removed under reduced pressure and compound E was obtained by flash chromatography (silica gel.DCM-Methanol 100:1-30:1 ), as a white hygroscopic powder, 703 mg, 87% yield.
  • Step 6 The imidazoline salt was dissolved in dry MeCN (3 mL) under nitrogen atmosphere, and then the guanidine free base of compound E (200 mg, 0.25 mmol, 0.4 equiv.) was added, followed by the addition of Et 3 N (0.26 mL, 1.86 mmol, 3.0 equiv.). Then the whole solution was heated to reflux for 12 h and cooled to room temperature. Add 1 HCI (20 mL) to the reaction solution and the mixture was extracted by CH 2 CI 2 (10 mL * 3). The combined organic layer was dried by Na 2 S0 4 . Solvent was removed under reduced pressure and PTC was obtained by flash chromatography (silica gel, DCM-Methanol 100:1-20 1 ), as a beige powder, 315 mg, 78% yield.
  • Benzo[b]thiophene-2-thiol and 3-methylbenzo[b]thiophene-2-thiol ((a) K. Hirai, K. Bessho, T. Kitagawa, H. Tomioka, J. Phys. Org. Chem. 2010, 23, 347-356; (b) D. Sperandio, H. J. Hansen, Helv. Chim. Acta 1995, 78, 765-771 ), 3-methyl-thiophene-2 -thiol, 5- methy!thiophene-2-thiol and 3,5-dimethylthiophene-2-thiol (B. H.Zhong. et al. Acyclic nucleoside phosphonate derivative and its pharmaceutical use.
  • Methyl 3-bromopropanoate 9b (1.37 mL, 12.5 mmol, 1 .2 equiv.) was added dropwise to a solution of 5-methoxy-1-methyl-1 H-benzo[d]imidazole-2-thiol (2.03 g, 10.4 mmol, 1.0 equiv.) in MeOH (10 mL) at room temperature. Then the mixture was stirred for 24 h at 82 oC. After the removal of solvent under reduced procure, the resulting residue was purified by flash chromatography to afford the desired compound as a red solid in quantitative yield.
  • Thienyl group is a heterocyclic aromatic ring that can be used as a bioisostere of a phenyl group in order to either improve efficacy or change specificity of binding in medicinal chemistry.
  • Some examples of commercially available drugs containing such a moiety are provided in Figure 1. initially, ⁇ -sulfinyl methyl ester 2a was chosen as the model substrate for reaction parameters screening (Table 1 and 2).
  • Base The choice of base is crucial to this transformation (Table 1 ).
  • One equivalent base was not efficient to promote the generation of su!fenate anion via retro-Michael reaction.
  • 20 equivalent of CsOH base was chose in term of reaction rate and enantioselectivity which led a slightly improvement than 10 equivalent of that.
  • bases with less basicity such as NaOH, KOH, and RbOH usually cannot furnish the completion of reaction and low yield of sulfoxide was observed.
  • strong base NaO'Bu as well as KO'Bu the reaction was too fast and most of the generated sulfenate anion intermediate underwent alkaline hydrolysis without trapping by the benzyl bromide electrophile. Therefore, the yield of desired sulfoxide product was still low.
  • reaction mixture was stirred at -70 °C and monitored by TLC. After 2a was completely consumed, reaction was quenched at 0 °C by addition of 1 aqueous HCI solution (1.5 mL) and extracted with CH 2 CI 2 (3 mL * 3). The combined organic layer was washed by brine and dried by Na 2 S0 4 , filtered and concentrated.
  • the sulfoxide 3a was obtained by flash chromatography (silica gel, hexane-ethyl acetate 10: 1-2:1 ), as colorless oil, 12.3 mg, 87% yield.
  • Example 2 The general procedure outlined in Example 2 was repeated using different starting materials The results of which are outlined in Table 5.
  • R 1 aryl, eteroaryl
  • R 2 aryl

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of formula (I): wherein R and A- are defined herein as a catalyst for making chiral heterocyclic sulfoxides and a method of producing enantioenriched sulfoxide in the presence of the said compounds.

Description

Catalysts for making Chira! Heterocyclic Sulfoxides
The listing or discussion of an apparently 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.
Optically active sulfoxides are extensively used as chiral auxiliaries, chiral ligands for meta! complexes and organocatalysts. This unique moiety is also found in several marketed drugs such as Esomeprazole (proton pump inhibitor), Armodafini! (eugeroic) and Sulindac (anti- inflammation). Currently, there are two main strategies for the synthesis of enantioenriched sulfoxides - nucleophilic substitution of non-racemic sulfinates using organometallic reagents (the Andersen method) and direct oxidation of prochiral sulfides catalyzed by metal complexes (Kagan and Moderna methods). Recently, a metal-free approach using chiral imidodiphiosphoric acid catalysts for highly enantioselective sulfide oxidation employing aqueous H202 has been demonstrated (e.g. see S. Liao, J. Am. Chem. Soc. 2012, 134, 10765-10768; and Z.-M. Liu, er a/., Synth. Cata!. 2012, 354, 1012-1022).
Due to the importance of such compounds, developments of catalytic and enantioselective methodologies with broad substrate scope are still highly desirable. In the classical Andersen method and its variants, the reactive sulfur center is electrophilic and a stoichiometric quantity of chiral auxiliaries is required (although recycling of auxiliary is possible in some cases). Recently, a complementary approach which is based on sulfenate anions (RSO") with a nucleophilic sulfur center has emerged as a viable method for enantio- and diasteroselective synthesis of sulfoxides. However, reports which exploit sulfenate anions in catalytic enantioselective synthesis of sulfoxides remain scant. Recent attempts with Cinchona alkaloid as a phase-transfer catalyst have been reported by Perrio and coworkers (see F. Gelat, et al., Org. Lett. 2011, 13, 3170-3173; and F. Gelat, er al., J. Sulfur Chem. 2013, 1-9), despite the high yield the ee-values do not exceed 60%. Asymmetric phase-transfer catalysis is a convenient, scalable and environmentally benign method to prepare compounds in high enantiopurity. Despite the success of several reported phase-transfer catalysts (PTCs) in the literature, it is still meaningful to design new ones with high level of stereocontrol. Recently, our group has developed structurally novel pentanidiums based on quaternized sp2-hybridized N- atoms as PTCs (see T. Ma, er al., J. Am. Chem. Soc. 2011 , 133, 2828-2831; Y. Y. Yang, et al., Org. Lett. 2012, 14, 4762-4765). Thiophene derivatives are important heteroaromatic compounds, which have been used prevalently in functional materials and pharmaceutical industry due to their distinct electronic and biological activities (Figure 1 ). Based on currently available methodologies for the synthesis of optically active sulfoxides, sulfoxides which contain thienyl group pose significant challenges (Figure 2; see also Reference Example 1). Although oxidation of sulfides is the most direct approach to sulfoxides, a sulfide with a thienyl substituent is vulnerable under the well-established Kagan method, leading to low yield and negligible enantioselectivity (Figure 1 a). On the other hand, in the classical Andersen approach, the use of organomagnesium reagents could potentially be problematic as sulfoxide that contains thiophene or furan could be displaced by such organometallic nucleophiles (Figure 1 b). Therefore, there remains a need for new methods of forming sulfoxides. Summary of Invention
In a first aspect of the invention, there is provided a compound of formula (1):
Figure imgf000003_0001
wherein:
A represents an anionic counterion; and
R represents a fragment of formula (II):
Figure imgf000004_0001
wherein:
the dotted line represents the point of attachment to the rest of molecule of formula
(I); and
each X independently represents Ci, Br or I.
In certain embodiments of the invention, each X is the same and may represent CI, Br or I. For example, all X groups may represent I.
In yet still further embodiments of the invention, the compound of formula (I) may be chrial. For example, the compound of formula (I) may be a compound of formula (la) or formula (lb):
Figure imgf000004_0002
Figure imgf000004_0003
In yet stili further embodiments of the invention, A may be an anionic counterion selected from the group consisting of CI", Br", Γ and F". In still further embodiments of the invention, the compound of formula (!) may be selected from:
(a) (4S,5S)-2-(((4Sr5S)-1 ,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenylimidazolidin- 2-ylidene)amino)-1 ,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenyl-4,5-dihydro-1H- imidazol-3-ium chloride;
(b) (4S,5S)-2-(((4S,5S)-1 ,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-4,5 diphenyiimidazolidin-
2- ylidene)amino)-1 ,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-4,5-diphenyl-4,5-dihydro-1 H- imidazol-3-ium chloride; and
(c) (4S,5S)-2-(((4S,5S)-1 ,3-bis(3,5-di-tert-butyl-2-iodobenzyl)-4,5-diphenylimidazolidin-2- ylidene)amino)-1 ,3-bis(3,5-di-tert-butyl-2-iodobenzyl)-4,5-diphenyl-4,5-dihydro-1 H-imidazol-
3- ium chloride.
In a second aspect of the invention, there is provided a use of a compound of formula (I) as described hereinbefore as a catalyst for a chemical reaction. For example, the chemical reaction may result in one or more enantioenriched products, in particular embodiments of the invention, the chemical reaction is the preparation of sulfoxides (e.g. enantioenriched sulfoxides). In a third aspect of the invention, there is provided a method for preparing an enantoenriched sulfoxide, said method comprising, reacting a compound of formula (III):
Figure imgf000005_0001
with a compound of formula (IV):
R3-X1 (IV)
in the presence of a catalytic amount of a compound of formula (i) as defined in any one of
Claims 4 to 6, a base and a solvent, to provide the enantioenriched sulfoxide, wherein:
Ri represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted alkyl group;
R2 represents and electron withdrawing group; and
R3 represents a substituted or unsubstituted alkyl group.
In certain embodiments, the solvent may comprise an ether (e.g. cyclopentyl methyl ether and/or diethyl ether). In still further embodiments, the solvent may further comprise water. In still further embodiments of the invention, the reaction may be conducted at a temperature of from -50°C to -80°C (e.g. from -60°C to -70°C). A catalytic amount of a compound of formula (I) may be from 0.0001 mol% to 20 mol%, such as from 0.001 to 2 mol%, e.g. 1 mol%.
In yet still further embodiments of the invention, the base may be a metal hydroxide, such as cesium hydroxide.
In yet still further embodiments of the invention, R2 may represent -C(0)2Me, -C(0)2Et, -0(0)2¾υ, -C(0)2Ph, S02Ph and -CN.
Drawings
The invention will be described with reference to the accompanying drawings.
Figure 1 depicts drugs containing thiophene moieties.
■■ Figure 2 depicts approaches for the assymetric synthesis of 2-thienyl sulfoxide 3a.
Figure 3 depicts the general procedure for the synthesis of chiral pentanidium salts (using the pentanidium salt 1c as an example).
Figure 4 depicts a working model hypothesis for the sulfenate anion intermediate.
Figure 5 depicts the single crystal structure of the (R)-form of compound 6q. Description
The variant based on the nucleophilic displacement of alkyl halides by sulfenate anion catalyzed with pentanidiums that we herein report is able to circumvent the aforementioned problems to give the optically active thienyl sulfoxide in high yield and enantioselectivity.
We began by investigating the enantioselective benzylation of 2-thienyl sulfenate anion generated in situ with pentanidiums as phase-transfer catalyst by using benzyl bromide as the electrophile. Preliminary variation of reaction parameters such as pentanidiums, sulfenate anion precursors, solvent, inorganic base and temperature were performed (refer to supporting information). Eventually, it was found that iodinated pentanidium 1d is the best catalyst, providing sulfoxide 3a with excellent enantioselectivity of 91 % ee (Table 2, entry 10). Eventually, it was found that iodinated pentanidium 1d is the best catalyst, providing sulfoxide 3a with excellent enantioselectivity of 91 % ee {Example 1 , Table 2, entry 10; n attempt to prepare compound 3a by direct sulfoxidation was not satisfactory), in contrast, commercially available phase-transfer catalysts were also tested and low enantioselectivity was obtained (below 15% ee, Reference Example 2, Table 3).
A variety of alkyl halides was examined as electrophile under optimized conditions (Table 4; Example 2). With 1 mol % of pentanidium 1d, the alky!ation of 2-thienyl suifenate anion with various alkyl halides produced the corresponding sulfoxides in good yields and excellent enantioselectivities. Benzyl bromides with electron-withdrawing and electron-donating substituents are well tolerated {entries 1-6). It should be noted that benzyl bromides caused erosion of enantioselectivity in the previous report of a related reaction by Perrio group (a) F. Gelat, J. Jayashankaran, J. F. Lohier, A. C. Gaumont, S. Perrio, Org. Lett. 2011, 13, 3170- 3173; b) F. Gelat, A.-C. Gaumont, S. Perrio, J. Sulfur Chem. 2013, 1-9.). The construction of stereogenic sulfoxides bearing allylic and propargylic substituents could also be achieved in a similar manner (entries 7-9). Moreover, the alkylation of 2-theinyl suifenate anion with alkyl iodides provided sulfoxides 3J-3I with good enantioselectivities (77-81% ee, entries 10- 12). These results indicated that both alkyl and benzyl groups can be installed using this methodology. For specific benzyl bromide derivatives with electron-withdrawing substituents (entries 3-4) and alkyl iodides (entries 10-12), brominated pentanidium 1 c provided sulfoxides with marginally better enantioselectivities.
The practicality of this newly developed methodology was demonstrated by scaling-up the reaction to one-mmol and reducing the catalyst loading to 0.25 mol % 1 d. The sulfoxide 6q was obtained in 85% yield with an excellent enantioselectivity of 91% ee (Example 3).
The scope of this reaction was further examined under the optimized conditions with various β-heteroaryl and aryl su!finyl methyl esters (4a-e, 5a-f) as suifenate anion precursors (Table 5). They participated in the reaction efficiently to provide the anticipated sulfoxides in high yields with good to excellent enantioselectivities. The methyl substituted 2-thienyl sulfinyl esters 4a was transformed to the corresponding highly enantioenriched sulfoxides 6a-f. Interestingly, the reaction between the suifenate anion generated from β-sulfinyl ester 4a and m-xyiene dibromide produced the bis-sulfoxide 6g in reasonable yield (87%, dl/meso = 4.75:1 ) and excellent enantioselectivity (>99% ee). Sulfoxides 6k-v containing benzothiophene were also obtained with excellent enantioselectivities. Benzimidazoie sulfoxide 7a, reminiscence of the drug esomeprazole, was obtained in high enantioselectivity (90% ee). Suifenate anions containing fury!, benzofuryl, pyridyl moieties can be tolerated and converted into the sulfoxides 7c-f with a slightly decrease in enantioselectivities. As far as we are aware, this methodology allows the widest range of heterocyclic sulfoxides to be obtained in high optical purity and yield.
Additional experiments were carried out to provide more insights into the reaction mechanism (Table 6). Based on the experimental study, a working mechanism was proposed {Figure 4). The inorganic base promotes the deprotonation of β-sulfinyl methyl ester 2a to give the corresponding caesium enolate, which leads to the generation of sulfenate anion and the release of methyl acrylate via a retro-Michael process even without PTC. However, the sulfenate anion intermediate will undergo alkaline hydrolysis under basic conditions in the absence of PTC. In the presence of the chiral PTC, cationic exchange and retro-Michael processes lead to a chiral ion pair A. It readily reacts with electrophile RX (X = Br) to afford the product 3a (path a). When the reaction was performed in the presence of PTC but not the alkyl halides, 2a produced thiophene sulfenate 8 via oxygen-Michael addition of sulfenate anion to methyl acrylate released during the retro-Michael process (path b). Moreover, using non-halogenated pentanidium 1 a and benzyl chloride, a less active electrophile, only sulfenate 8 instead of sulfoxide 3a was observed (path b). However, it is noteworthy that sulfoxide 3a can be formed when halogenated pentanidiums were used as catalysts with benzyl chloride (path a). These results indicate the ability of halogenated pentanidiums to activate both the electrophile and the sulfenate anion nucleophile.
In summary, we have described a highly enantioseiective alkyiation of sulfenate anions to prepare enantioenriched sulfoxides using halogenated pentanidiums as catalysts. These heterocyclic sulfoxides could potentially be used as chiral ligands, chiral organocatalyst or bioactive molecules. Moreover, the work demonstrates the possibility of incorporating halogen bond as primary non-covalent interaction when designing organocatalysts.
Thus, there is provided a compound of formula (I):
Figure imgf000008_0001
wherein:
A represents an anionic counterion; and R represents a fragment of formula (II):
Figure imgf000009_0001
wherein:
the dotted line represents the point of attachment to the rest of molecule of formula
(I); and
each X independently represents CI, Br or I.
When used herein "anionic counterion" may refer to any anionic species that can form an ion pair with the positive charge on one of the nitrogen atoms of the compound of formula (I). For example, the anionic counter ion may be the anion of a carboxylic acid or it may be an anionic halogen ion (e.g. Br", Γ, F" or, more particularly, CI"). The substituent X may be the different or, more particularly, the same. For example, when each X is the same, X may represent one of CI, Br or, more particularly, i.
As noted above, the compounds of the current invention may be particularly useful as catalysts in enentioselective reactions. As such, the compound of formula (I) may be chiral. For example, the compound of formula (1) may be a compound of formula (la) or formula (lb):
Figure imgf000010_0001
In particular embodiments of the invention that may be mentioned herein, the compound of formula (I) may be selected from:
(a) (4S,5S)-2-(((4S,5S)-1 ,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenylimidazolidin- 2-yifdene)amino)-1 ,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenyl-4,5-dihydro-1 H- imidazol-3-ium chloride;
(b) (4S,5S)-2-(({4S,5S)-1 ,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-4,5 diphenylimidazolidin-
2- ylidene)amino)-1 ,3-bis(2-bromo-3,5-di-tert-buty!benzyl)-4,5-diphenyl-4,5-dihydro-1H- imidazol-3-ium chloride; and, more particularly,
(c) (4S,5S)-2-(((4S,5S)-1 ,3-bis(3,5-di-tert-butyl-2-iodobenzyl)-4,5-diphenylimidazolidin-2- ylideneJamino^l .S-bisfS.S-di-tert-butyl^-iodobenzylH.S-diphenyl^.S-dihydro-I H-imidazol-
3- ium chloride. As described hereinbefore, the compound of formula (I) may be used as a catalysts for a chemical reaction. Thus, in a second aspect of the invention, there is provided a use of a compound of formula (I) as described hereinbefore as a catalyst for a chemical reaction. For example, the chemical reaction may result in one or more enantioenriched products. In particular embodiments of the invention, the chemical reaction is the preparation of sulfoxides (e.g. enantioenriched sulfoxides).
When used herein, the term "enantioenriched" is intended to refer to a product of a chemical reaction involving the compound of formula (I), wherein said product has an enantiomeric ratio that is greater than 50 : 50 but less than 100 : 0. In other words, the enantioenriched compound is not racemic and may, for example, have an enantiomeric excess (ee) of from 50% to 99.99% ee. In a third aspect of the invention, there is provided a method for preparing an enantoenriched sulfoxide, said method comprising, reacting a compound of formula (III):
Figure imgf000011_0001
with a compound of formula (IV): R3-X1 (IV)
in the presence of a catalytic amount (e.g. from 0.0001 mol% to 20 mol%, such as from 0.001 to 2 mol%, i.e. 1 mol%) of a compound of formula (I) as defined in any one of Claims 4 to 6, a base and a solvent, to provide the enantioenriched sulfoxide, wherein:
R1 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted alky! group;
R2 represents and electron withdrawing group; and
R3 represents a substituted or unsubstituted alkyl group.
Unless otherwise stated, the term "aryl" when used herein includes C6.1 (such as C6.io) 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. C6.14 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 naphthyl or, more particularly, phenyl.
Unless otherwise stated, the term "alkyl" refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl)hydrocarbyl radical. Where the term "alkyl" refers to an acyclic group, it is preferably C O alkyl and, more preferably, C -6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), prop-1-eneyl, 2- methylisoprop-1-eneyl, butyl (e.g. branched or unbranched butyl), but-2-ynyl, pentyl ormethyl). Where the term "alkyl" is a cyclic group (which may be where the group "cycloalkyl" is specified), it is preferably C3.12 cycloaikyl and, more preferably, C5.io (e.g. C5-7) cycloalkyl.
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 4 (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, benzimidazoiyi, 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, benzomorpho!inyl, benzoselenadiazoiyl (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, pyridy!, pyrimidinyl, pyrrolyl, quinazo!inyl, quinoiinyl, 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-thiadiazolyi and 1 ,3,4-thiadiazolyi), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1 ,2,3-triazol l, 1 ,2,4-triazoiyl 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, quinoiinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinoiinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl. Particularly preferred heteroaryl groups include monocylic heteroaryl groups (e.g. furan, and thiophene). When used herein a "substituted" group refers to a group (e.g. an aryl, a heteroaryl or an alkyl group as defined hereinbefore) substituted with one or more substituents selected from halogen, an aikyl group, phenyl (which may be unsubstituted or substituted by halogen, -OAIky!, -COAIkyl, -C{0)2Alkyl, -S02alkyl and -CN), naphthyl (which may be unsubstituted or substituted by -OAIkyl, -COAIkyl, -C(0)2Alkyl, -S02alkyl and -CN), -OAIkyl, -COAIkyl, -C(0)2Alkyl, -S02alkyl and -CN.
The term "halogen", when used herein, includes fluorine, chlorine, bromine and iodine. In certain embodiments of the invention, the solvent may comprise an ether (e.g. cyclopentyl methyl ether and/or diethyl ether). In still further embodiments, the solvent may further comprise water.
As mentioned hereinbelow, the reaction may be conducted at a temperature of from -50°C to -80°C {e.g. from -60°C to -70°C).
In yet still further embodiments of the invention, the base may be a metal hydroxide, such as cesium hydroxide. When used herein, the term "electron withdrawing group" will be understood to mean a moiety that enables the deprotonation of the carbon atom alpha- to said electronwithdrawing group. Examples of electron withdrawing groups that may be mentioned herein includes -C(0)2 e, -C(0)2Et, -C(0)2lBu, -C(0)2Ph, S02Ph and -CN, that is R2 may be any of these groups.
Advantages offered by the compound of formula (!) are listed below.
1. Optically active sulfoxides have extensive applications as chiral ligands, chiral organocatalyst, synthetic intermediates and bioactive drugs. The importance and the unique property of sulfoxide compounds promote the developing the synthetic approaches to them. Nowadays, there are two main strategies to synthesize enantioenriched sulfoxides: the classical Andersen method and the Kagan-Modena method. Many modification based on these two approaches also have been developed. However, the development of catalytic and enantioselective methodologies with broad substrate scope and using non-metallic chiral catalysts is still highly desirable, which has been developed herein.
2. Recently, the new emerging approach using the nucleophilic sulfenate anion species is potentially viable strategy for enantio- and d (stereoselective synthesis of sulfoxides. However, reports which employing the sulfenate anion in catalytic enantioselective synthesis of sulfoxide is still scant and only moderate results were obtained. We describe the surprisingly effective asymmetric alkylation reaction of a sulfenate anion intermediate using a pentanidium phase-transfer catalyst (i.e. the compound of formula (I)) for the synthesis of chiral heterocyclic sulfoxides.
3. In this methodology, a catalytic and highly enantioselective synthesis of various chiral heterocyclic sulfoxides using 1 mol % of pentanidium phase-transfer catalyst was achieved. The chiral heterocyclic sulfoxide which might not be compatible with the strong oxidation and organometallic reagents can be efficiently obtained with high yields and good to excellent enantioselecttvities with low loading of phase-transfer catalyst.
4. The chiral heterocyclic sulfoxides made using the compound of formula (1) could potentially be used as chiral organocatalyst, chiral ligand for metal complexes, biologically active molecules or drugs.
EXPERIMENTAL General
1 H and 13C N R spectra were recorded on Bruker AV-300 (300 MHz), BrukerAvance III 400 (400MHz) (100 MHz) spectrometer, 500 MHz Bruker DRX NMR spectrometer or AMX500 (500MHz) spectrometer. Chemical shifts are recorded as δ in units of parts per million (ppm). The residual solvent peak was used as an internal reference. 19F NMR was performed on a Bruker Avance 111 400 (400MHz) spectrometer. Low resolution mass spectra (LRMS) were obtained on the ThermoFinnigan PolarisQ MS and ThermoFinnigan LCQ Fleet MS; High resolution mass spectra (HRMS) were obtained on the Q-Tof Premier mass spectrometer (Waters Corporation). LRMS and HRMS were reported in units of mass of charge ratio {m/z). Enantiomeric excess values were determined by HPLC analysis on Shimadzu LC-20AT and LC-2010CHT HPLC workstations. Optical rotations were measured in CHCI3 using a 1 mL cell with a 1 dm path length on a Jasco P-1030 polarimeter with a sodium lamp of wavelength 589 nm and reported as follows:(c = g/100 mL, solvent). Melting points (mp) were measured in OptiMelt MPA100 equipment and uncorrected. IR spectra were recorded with neat solid/liquid samples on a Shimadzu IR- Prestige-21 spectrometer and reported in wave numbers (cm'1). X-ray crystallography analysis was performed on Bruker XS APEX X- ray diffractionmeter. Flash chromatography separations were performed on Merck 60 (0.040 - 0.063mm) mesh silica gel. Analytical thin- layer chromatography (TLC) was performed on Merck 60 F254 silica gel plates. Visualization was performed using a UV lamp or potassium permanganate stain. Materials
THF were distilled over sodium/benzophenone under Nz atmosphere. Toluene, Acetonitrile and Dichloromethane were distilled over CaH2 under N2 atmosphere. The mercaptans were purchased from commercial suppliers or synthesized according to the literature procedures and used directly without further purification. Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated. Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet. All compounds synthesized were stored in a -30 °C freezer.
Preparations Preparation
Syntheses and Characterization of Chiraf Pentanidium Salts
Representative procedure for chlorination or bromination of arene ((a) K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horaguchi, Chem. Lett. 2003, 32, 932-933; b) K. Kawamura, H. Fukuzawa, M. Hayashi, Bull. Chem. Soc. Jpn. 2011 , 84, 640-647): A mixture of 3,5- di-tert-butyl toluene (5.0 g, 24.4 mmol, 1.0 equiv.), FeCI3 (0.78 g, 4.9 mmol, 0.2 equiv.) and NBS (4.56 g, 25.6 mmol, 1.05 equiv.) in dry CH3CN (50 mL) was stirred at 82 °C for 12 h, and the resulting solution was cooled to room temperature and then evaporated. The crude product was purified by silica gel column chromatography (hexane as the eluent) to give 2- bromo-1 ,5-di-tert-butyl-3-methylbenzene (6.83 g, 24.0 mmol) as colorless oil in 98% yield.
Preparation 2
Representative procedure for iodination of arene; Procedure modified from S. Stavber, P. Kralj, M. Zupan, Synthesis 2002, 15 3-15 8.
To a solution of 3.5-di-tert-butyl toluene (4.08 g, 20 mmol, 1.0 equiv.) in eCN (100 mL) were added l2 (3.8 g, 15.0 mmol, 0.75 equiv.) and Seiectfluor (5.3 g, 15.0 mmol, 0.75 equiv.) and the reaction mixture was stirred at 60 °C for 5 h. The solvent was removed under reduced pressure and the crude mixture was dissolved in CH2CI2 (100 mL). After the filtration, the filtrate was washed with aqueous 10 % Na2S203 «5H20 ( 00 mL) and H20 (100 mL), and dried (Na2S0 ). The solvent was evaporated, and the crude product were purified by flash chromatography over silica gel (hexane), followed by distillation under reduced pressure (colourless oil, 3.21 g, 74% isolated yield) with the recovery of 3,4-di-tert- butyltoluene (1.4 g, 6.86 mmol). Preparation s
Syntheses of 1-(bromomethyl)-3,5-di-tert-butyl-2-iodobenzene:
Modified from procedures reported in: a) K. Hirai, K. Bessho, T. Kitagawa, H. Tomioka, J. Phys. Org. Chem. 2010, 23, 347- 356; and b) D. Sperandio, H. J. Hansen, Helv. Chim. Acta 1995, 78, 765-771.
To a stirred solution of 1 ,5-di-tert-butyl-2-iodo-3-methyibenzene (4.17 g, 12.6 mmol, 1.0 equiv.) in H2S04 (6.86 mL), AcOH (21 mL), and Ac20 (46 mL) was slowly added KMn04 (4.98 g, 31.5 mmol, 2.5 equiv.) at 40 °C over a period of 4 h and the mixture was stirred for 1 day at the same temperature. The mixture was poured into H2O and extracted with Et20. The ethereal layer was washed with 10% NaOH solution and brine, dried over anhydrous Na2S04, and the solvent was removed under reduced pressure. The residue was chromatographed through a column of silica gel using hexane-CH2CI2 (2:1 ) as the eluent to give 3,5-di-tert-buty!-2-iodobenzyl acetate(1.51 g, 3.90 mmol) as a yellow viscous liquid in 31% crude yield.
To a stirred solution of this acetate (1.51 g, 3.90 mmol 1.0 equiv.) in MeOH (20 mL) was added K2C03 (270 mg, 1.95 mmol, 0.5 equiv.) and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of 2 M hydrochloric acid. The mixture was extracted with ether, and the organic solution was washed with brine, dried over anhydrous Na2S04, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (silica gel, hexane-ethyl acetate 20:1-5:1 ) afford the product to give (3,5-di-tert-buty!-2-iodophenyl)methanol (1.24 g, 3.58 mmol) as a white solid in 92% yield.
(3,5-di-tert-butyl-2-iodophenyl)methanol (984 mg, 2.84 mmol, 1.0 equiv.) was suspended in a vigorously stirred solution of glacial AcOH (5.7 mL) and HBr (48% wt in H20, 1.54 mL, 10 equiv.). The suspension was heated up to 100 °C for 1 h. Then the mixture was cooled to room temperature and poured onice-water and stirred again for 10 min. The mixture was extracted with ether, and the organic solution was washed with brine, dried over anhydrous Na2S04, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography using hexane as an eluent to afford the product l-(bromomethyl)- 3,5- di-tert-butyl-2-iodobenzene(1.0 g, 2.45 mmol) as colourless oil in 87% yield.
Example 1 Representative procedure for the syntheses of chirai pentanidium salts (taking the pentanidium salt 1c as an example):
Step 1 : To a solution of chirai diamine A (1.23 g, 5.8 mmol, 1.0 equiv.) and K2C03 (1.77 g, 12.8 mmol, 2.2 equiv.) in MeCN (15 mL), was added a solution of 2-bromo-3,5-di-tert- butylbenzyl bromide (4.30 g, 11.9 mmol, 2.05 equiv.) in MeCN (15 mL) by using a syringe pump during 1 h, and then the reaction mixture was stirred for 24 h at room temperature (monitored by TLC). After diamine A was completely consumed, reaction was quenched by water (20 mL) and extracted with CH2CI2 (30 mL * 3). The combined organic layer was washed by brine and dried by Na2S04. Solvent was removed under reduced pressure. Compound B was obtained by flash chromatography (silica gel, hexane-ethyl acetate 50:1- 30:1 ), as a white solid, 3.55 g, 79% yield.
Step 2: A 50 ml flask was charged with 1.0 mL CH2CI2, compound B (522 mg, 0.67 mmol, 1.0 equiv.), and K2C03 (205 mg, 1 ,48 mmol, 2.2 equiv.) in 1.5 mL H20. The resulting mixture was stirred vigorously at 0 °C, followed by the dropwise addition of an anhydrous CH2CI2 solution of triphosgene (1.0 M, 67 mg, 0.22 mmol, 0.33 equiv.). After the addition, the mixture was warmed to room temperature and further stirred for 2 h to complete the reaction. The reaction mixture was then extracted with CH2CI2 (5 mL χ 3). The combined organic layer was washed by brine and dried by Na2S04. Solvent was removed under reduced pressure. Compound C was obtained by flash chromatography (silica gel, hexane-ethy! acetate 50:1- 30:1 ), as a white solid, 515 mg, 95% yield.
Step 3: To a solution of compound C (515 mg, 0.64 mmol, 1.0 equiv.) in 3.0 mL o-xylene was added Lawesson's reagent (518 mg, 1.28 mmol, 2.0 equiv.) under nitrogen atmosphere. Then the whole solution was heated to 145 °C for 24 h and cooled to room temperature. Upon the completion of compound C on TLC, the whole solution was directly loaded on a column. Firstly, all the o-xylene was allowed to drain by gravity and then hexane/ethyl acetate ( 00:1- 20:1 ) was used to flush out compound D as a pale-yellow foam, 508 mg, 96% yield.
Step 4: A 100 mL RBF was charged with a solution of D (508 mg, 0.62mmol, 1.0 equiv.) in toluene (3 mL) with a condenser under N2 atmosphere. (COCI)2 (0.43 mL, 4.97 mmol, 8.0 equiv.) was added via syringe in one portion. The mixture was refluxed overnight until D was completely reacted. Toluene was removed under reduced pressure and solid imidazoline salt was obtained for the next step without any purification. (Imidazoline salt is air and moisture sensitive, which should be stored under nitrogen atmosphere or vacuum.)
Step 5: To a solution of B (775 mg, 1 mmol, 1.0 equiv.) in dry MeCN (5 mL) under nitrogen atmosphere was added BrCN (106 mg, 1 mmol, 1.0 equiv.). The whole solution was heated to reflux for 12 h and cool to room temperature. Then solvent was removed under reduced pressure and compound E was obtained by flash chromatography (silica gel.DCM-Methanol 100:1-30:1 ), as a white hygroscopic powder, 703 mg, 87% yield. A mixture of theguanidinium salt E (0.87 mmol 1.0 equiv.) and 3 NaOH (13.05 mmol, 15 equiv.) in CH2CI2 (13 mL) was vigorously stirred for 15 min at room temperature. The mixture was then extracted with CH2CI2 (13 mL * 3). The combined organic phases were washed with water (20 mL), dried over MgS0 and concentrated to dryness under reduced pressure to provide the corresponding guanidine free base quantitatively as white solid.
Step 6: The imidazoline salt was dissolved in dry MeCN (3 mL) under nitrogen atmosphere, and then the guanidine free base of compound E (200 mg, 0.25 mmol, 0.4 equiv.) was added, followed by the addition of Et3N (0.26 mL, 1.86 mmol, 3.0 equiv.). Then the whole solution was heated to reflux for 12 h and cooled to room temperature. Add 1 HCI (20 mL) to the reaction solution and the mixture was extracted by CH2CI2 (10 mL * 3). The combined organic layer was dried by Na2S04. Solvent was removed under reduced pressure and PTC was obtained by flash chromatography (silica gel, DCM-Methanol 100:1-20 1 ), as a beige powder, 315 mg, 78% yield.
1,5-di-tert-butyl-2-chloro-3-methy1benzene Colourless oil; 80% yield; 1H NMR (400 MHz, CDCI3): δ = 7.35 (d, J - 2.4 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1 H), 2.42 (s, 3H), 1.53 (s, 9H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 148.49, 145.79, 137.15, 131.09, 125.93, 122.57, 36.52, 34.53, 31.36, 29.90, 21.99; IR: 2962, 2872, 1463, 1240, 1037, 873, 732 cm"1; LRMS (El) m/z 238.1 [M] +.
1-{bromomethyl)-3,5-di-tert-buty[-2-chlorobenzene[K. Kawamura, H. Fukuzawa, M. Hayasht, Bull. Chem. Soc. Jpn. 2011, 84, 640-647] Colourless oil; 93% yield; 1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1H), 4.66 (s, 2H), 1.51 (s, 9H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCI3): δ = 149.37, 146.88, 136.24, 131.06, 126.28, 125.70, 36.74, 34.70, 33.21 , 31.25, 29.87; IR: 2964, 1363, 1215, 1039, 881 cm-1
2-bromo-1, 5-di-tert-butyl-3-methylbenzene Colourless oil; 98% yield; 1 HNMR (400 MHz, CDCI3): δ = 7.33 (d, J = 2.5 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 2.44 (s, 3H), 1.54 (s, 9H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCI3): δ = 149.18, 147.36, 139.22, 125.94, 122.91 , 122.61 , 77.32, 77.00, 76.68, 37.28, 34.56, 31.29, 30.10, 25.65; LRMS (El) m/z 283.1 [M] +.
2-bromo-1-{bromomethyl)-3,5-di-tert-butylbenzene [K. Kawamura, H. Fukuzawa, M. Hayashi, Bull. Chem. Soc. Jpn. 201 1 , 84, 640-647] Colourless oil; 83% yield; 1H NMR (300 MHz, CDC!3): δ = 7.45 (d, J - 2,5 Hz, 1 H), 7.33 (d, J - 2,5 Hz, 1 H), 4,72 (s, 2H), 1.55 (s, 9H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCi3): δ = 150.08, 148.48, 138,11 , 126.47, 125.97, 122.13, 77.42, 77.00, 76.58, 37.53, 36.78, 34.72, 31.19, 30.11.
1,5-di-tert-butyl-2-iodo-3-methylbenzene Colourless oil; 74% yield; 1H NMR (400 MHz, CDC ): δ - 7,29 (d, J = 2.4 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 2,53 (s, 3H), 1.61 (s, 9H), 1.31 (s, 9H); 3C NMR (100 MHz, CDCI3): δ = 150.27, 150.15, 142.97, 124.93, 122.55, 100.01 , 37.80, 34.54, 32.64, 31.23, 30.42; LRMS (El) m/z 330.0 [M] +.
(3,5-di-tert-butyl-2-iodophenyl)methanol White solid; 92% yield; mp: 89.9-91.0 °C; H NMR (400 MHz, CDCI3): 5 = 7.44 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 4.76 (d, J = 6.4 Hz, 2H), 2.28 (t, J = 6.6 Hz, 1 H), 1.61 (s, 9H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCI3): δ = 150.87, 150.31 , 143.86, 124.70, 124.20, 96.61 , 72.28, 37.86, 34.76, 31 ,23, 30.44.
1-(bromomethyl)-3,5-di-tert-butyl-2-iodobenzene Colourless oil; 87% yield; 1H NMR (400 MHz, CDCI3): δ = 7.41 (d, J = 2.5 Hz, 1 H), 7,36 (d, J = 2.5 Hz, 1H), 4.79 (s, 2H), 1.60 (s, 9H), 1.31 (S, 9H); 3C MR (100 MHz, CDCI3): δ = 151.45, 151.07, 141.56, 125.75, 125.54, 98.71 , 43.80, 38.09, 34,70, 31.14, 30.48; IR: 2962, 1639, 1394, 1363, 1263, 1121 , 1002, 881 , 732 cm"1.
(1S,2S)-N1 ,N2-bis(3,5-di-tert-butylbenzyl)-1,2-diphenylethane-1,2 diamine White solid; 83% yield; mp: 109.7-111.1 °C; [a]£ - + 6.4 (c 0.64, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.28 (t, J = 1.7 Hz, 2H), 7,16 (dd, J = 6.2, 4.5 Hz, 6H), 7,06 (dd, J = 9.4, 1 ,8 Hz, 8H), 3.73 (s, 2H), 3.63 (d, J = 13.0 Hz, 2H), 3.49 (d, J = 13.0 Hz, 2H), 1.29 (s, 36H); 13C NMR (100 MHz, CDCI3): δ ~ 150.53, 141 .48, 139.62, 128.08, 127.87, 126.80, 122.39, 120.73, 68.44, 52.08, 34.73, 31.48; IR: 3419, 2962, 1627, 1452, 1361 , 1247, 1 199, 698 cm"1; HRMS (ESI) calcd for C^Heo^ m/z [M+H] +: 617.4835; found: 617.4835. (1 S,2S)-N1,N2-bis(3,5-di-tert-butyl-2-chlorobenz^
Colourless oil; 78% yield; [a]g = + 20.3 (c 1.24, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.33 (d, J = 2.4 Hz, 2H), 7.20 -7.12 (m, 6H), 7.09 (d, J = 1.8 Hz, 2H), 7.07 (dd, J = 4.1 , 1.9 Hz, 4H), 3.79 (d, J = 13.6 Hz, 2H), 3.66 (s, 2H), 3.56 (d, J = 13.6 Hz, 2H), 2.64 (s, 2H), 1 .45 (s, 18H). 1.26 (s, 18H); 13C NMR (100 MHz, CDCI3): 0 = 148.41 , 145.89, 141.21 , 138.61 , 130.64, 128.02, 127.91 , 126.84, 125.72, 123.53, 68.41 , 50.84, 36.51 , 34.59, 31.33, 29.96; IR: 3419, 2962, 2360, 1653, 1454, 1394, 1363, 1265, 1199, 1035, 879, 738, 700 cm"1; HRMS (ESi) calcd for C44H58C!2 2 m/z [M+H]+: 685.4055; found: 685.4050.
(1 S,2S)-N1,N2^is(2-bromo-3,5-di-tert-butylbenzyl)-1 ,2-diphenylethane-1,2-diamine
White hygroscopic foam; 79% yield; [α]£ = -22.1 (c 1.8, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.38 (d, J = 2.5 Hz, 2H), 7.24-7.1 1 (m, 10H), 7.08 (d, J = 2.5 Hz, 2H), 3.84 (d, J = 13.6 Hz, 2H), 3.71 (s, 2H), 3.63 (d, J = 13.6 Hz, 2H), 2.72 (s, 2H), 1.53 (s, 18H), 1.30 (s, 18H); 1 C NMR (100 MHz, CDCI3): δ = 149.00, 147.33, 141.10, 140.31 , 128.01 , 127.92, 126.84, 126.07, 123.94, 121.85,68.22, 53.60, 37.27, 34.57, 31.26, 30.17; IR: 3415, 2964, 1629, 1458, 1396, 1363, 1199, 1014 cm"1; HRMS (ESI) calcd for C44H5eBr2N2 m/z [M+H] +: 775.3025; found: 775.3007.
(1S,2S}-N1,N2-bis(3,5-di-tert-butyI-2-iodobenzyl)-1 ,2-diphenylethane-1,2-diamine White foam; 94% yield; = +18.2 (c 1.72, CHCI3); 1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 2.3 Hz, 2H), 7.16 (dt, J = 13.7, 4.9 Hz, 10H), 7.00 (d, J = 2.3 Hz, 2H), 3.79 (d, J - 13.5 Hz, 2H), 3.69 (S, 2H), 3.63 (d, J = 13.5 Hz, 2H), 2.74 (s, 2H), 1.55 (s, 18H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCI3): δ = 150.19, 149.94, 143.63, 141.14, 128.16, 127.98, 126.88, 125.60, 123.85, 98.67, 68.12, 58.98, 37.85, 34.55, 31 .23, 30.55; IR: 3305, 2953, 2304, 1587, 1556, 1454, 1392, 1361 , 1 165, 1105, 999, 878 cm"1; HRMS (ESI) calcd for C^H^ z m/z [M+H] +: 869.2768; found: 869.2767.
(4S,5S)-1 ,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-one White solid;>99% yield; mp: 144.5-146.3 °C; = - 53.7 (c 1.2, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.25 (ddt, J = 8.8, 3.5, 1 .7 Hz, 8H), 7.01 - 6.96 (m, 4H), 6.96 (d, J = 1.7 Hz, 4H), 5.12 (d, J = 14.5 Hz, 2H), 3.99 (s, 2H), 3.62 (d, J = 14.5 Hz, 2H), 1 .28 (s, 36H); 13C NMR (100 MHz, CDCI3): δ = 159.85, 150.82, 139.41 , 135.70, 128.66, 128.14, 127.27, 122.98, 121.07, 65.34, 46.30, 34.70, 31.41 ; IR: 2962, 1697, 1697, 1600, 1444, 1361 , 1249, 1201 , 948, 702. cm"1; HRMS (ESI) calcd for C^H^O /z [M+H] +: 643.4627; found: 643.4631.
(4S,5S)-1,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenylimidazolidin-2-one White solid; 78% yield; mp:100.2- 101.3 °C; [α]? = -77.8 {c 0.6, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.30 (d, J = 2.3 Hz, 2H), 7.27-7.18 (m, 6H), 7.03 (dd, J = 7.3, 2.0 Hz, 4H), 6.85 (d, J = 2.3 Hz, 2H), 5.11 (d, J = 14.8 Hz, 2H), 4.02 (d, J = 14.8 Hz, 2H), 3.94 (s, 2H), 1.45 (s, 18H), 1.19 (s, 18H); 13C NMR (100 MHz, CDCI3): δ = 159.30, 148.42, 146.19, 139.92, 134.81 , 130.69, 128.71 , 128.06, 127.08, 126.24, 124.18, 66.09, 45.42, 36.52, 34.49, 31.21 , 29.8; IR: 3053, 2966, 2304, 1701 , 1419, 1037 cm"1; HRMS (ESi) calcd for
Figure imgf000021_0001
m/z [M+H] +: 711.3848; found: 711.3849.
{4S,5S)-1,3-bis{2-bromo-3,5-di-tert-buty!benzyi)-4,5-diphenylimidazolidin-2-one
Colorless oil; 95% yield; = -69.8 (c 1.57, CHCI3); 1H NMR (400 MHz, CDCi3): δ = 7.39- 7.18 (m, 8H), 7.07 (dd, J = 6.4, 3.1 Hz, 4H), 6.82 (d, J = 2.4 Hz, 2H), 5.13 (d, J - 14.8 Hz, 2H), 4.09 (d, J = 14.8 Hz, 2H), 3.96 (s, 2H), 1.50 (s, 18H), 1.18 (s, 18H); 53C NMR (100 MHz, CDCIs): δ = 159.23, 149.05, 147.74, 139.92, 136.60, 128.75, 128.06, 127.07, 126.39, 124.59, 121.60, 66.08, 48.23, 37.32, 34.50, 31.15, 30.04; IR: 2962, 1697, 1629, 1460, 1265, 1201 , 1016, 881 cm"1; HRMS (ESI) calcd for C45H56Br2N20 m/z [M+H] +: 801.2817; found: 801.2822.
(4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidine-2-thione Pale yellow foam; >99% yield; = - 152.10 (c O.95, CHCI3);1H NMR (400 MHz, CDCI3): δ = 7.32-7.24 (m, 8H), 7.01 (d, J = 1.6 Hz, 4H), 6.97 (dd, J = 7.7, 1.6 Hz, 4H), 5.88 (d, J = 14.6 Hz, 2H), 4.24 (s, 2H), 3.74 (d, J = 14.6 Hz, 2H), 1.27 (s, 36H); 3C NMR (100 MHz, CDCI3): δ = 182.08, 150.96, 139.18, 135.14, 129.02, 128.57, 127.06, 122.88, 121.40, 68.73, 49.72, 34.75, 31.45; IR: 2964, 2904, 2304, 1598, 1448, 1417, 1363, 1300, 1219, 1199, 1080, 742 cm"1; HRMS (ESI) calcd for C45H58N2S m/z [M+H] +: 659.4399; found: 659.4401. (4S,5S)-1,3-bis(3,5-di-tert-butyl·2-chlorobenzy!)-4,5-diphenylimidazolidine-2-thione
Colourless oil; 78% yield; [a]J? = -164.64 (c 2.2, CHCI3); Ή NMR (400 MHz, CDCI3): δ = 7.33 (d, J = 2.3 Hz, 2H), 7.29 (dd, J = 5.0, .6 Hz, 6H), 7.06 (dd, J = 6.3, 2.8 Hz, 4H), 6.98 (d, J = 2.2 Hz, 2H), 5.79 (d, J = 14.9 Hz, 2H), 4.23 (d, J = 16.6 Hz, 4H), 1.44 (s, 18H), 1.22 (s, 18H); 13C NMR (100 MHz, CDCI3): δ = 182.51 , 148.57, 146.29, 139.36, 134.30, 130.69, 129.02, 128.44, 126.81 , 126.02, 124.39, 69.52, 48.62, 36.52, 34.52, 31.23, 29.78; IR: 3053, 2964, 2870, 1463, 1423, 1363, 1200, 1037 cm"1; HRMS (ESi) caicd for C45H56CI2N2S m/z [M+H] +: 727.3620; found: 727.3620.
(4S,5S)-1,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-4,5-diphenylirnidazolidine-2-thione
Pale yellow foam; 96% yield; [α] - -145.0 (c 2.02, CHCI3); 1H N R (400 MHz, CDCI3): δ = 7.33 (d, J = 2.4 Hz, 2H), 7.31 -7.26 (m, 6H), 7.14-7.02 (m, 4H), 6.95 (d, J = 2.4 Hz, 2H), 5.77 (d, J = 15.0 Hz, 2H), 4.32 (d, J = 15.0 Hz, 2H), 4.22 (s, 2H), 1.47 (s, 18H), 1.20 (s, 18H); 13C NMR (100 MHz, CDCI3): δ = 182.65, 149.23, 147.83, 139.32, 136.11 , 129.09, 128.48, 126.86, 126.07, 124.83, 121.59, 69.58, 51.49, 37.36, 34.58, 31.22, 30.04; IR: 2964, 1421 , 1396, 1263, 1199, 1016, 883 cm"1; HRMS (ESI) calcd for C^HseBr^S m/z [M+H] +: 817.2589; found: 817.2587.
(4S,5S)- ,3-bis(3,5-di-tert-butyl-2-iodobenzyl)-4,5-diphenylimidazolidine-2-thione: A 5 mL flask was charged with 1.5 ml_ CH2CI2, (1 S,2S)-N1 ,N2-bis(3,5-di-tert-butyl-2-iodobenzy!)- 1 ,2- diphenylethane-1 ,2-diamine (305 mg, 0.35 mmol, 1.0 equiv.) and K2C03 (106 mg, 0.77 mmol, 2.2 equiv.) in 1.5 mL H20. The resulting mixture was stirred vigorously at 0 oC, followed by the dropwise addition of a solution of thiophosgene (1.0 M, 29.6 μ!_, 0.39 mmol, 1.1 equiv.) in anhydrous CH2CI2. After the addition, the mixture was warmed to room temperature and further stirred for 2 h to complete the reaction. The reaction mixture was then extracted with CH2CI2 (5 mL * 3). The combined organic layer was washed by brine and dried by Na2S04. After removal of solvent under reduced pressure, the residue was subjected to flash chromatography (silica gel, hexane-ethyl acetate 50:1-30:1 ) to afford the product as colorless oil in 91 % yield; [a]£ = -126.4 (c 0.36,CHCI3); 1H NMR (400 MHz, CDCS3): δ = 7.30 (dd, J = 4.2, 2.3 Hz, 4H), 7.10 (dd, J = 6.5, 3.0 Hz, 2H), 6.91 (d, J = 2.4 Hz, 1 H), 5.74 (d, J = 15.1 Hz, 1H), 4.43 (d, J = 15.2 Hz, 1H), 4.22 (s, 1 H), 1.51 (s, 8H), 1.19 (s, 8H); 13C NMR (100 MHz, CDCI3): δ = 182.99, 150.63, 150.14, 139.35, 139.21 , 129.13, 128.45, 126.94, 125.28, 124.65, 97.89, 69.64, 57.23, 37.90, 34.52, 31.15, 30.40; IR: 2964, 2870, 1633, 1556, 1487, 1454, 1396, 1361 , 1280, 1234, 1165, 1001 , 731 cm"1; HRMS (ESI) calcd for C45H56I2 2S m/z [M+H] +: 911.2332; found: 911.2335. (4S,5S)-1-(3,4-di ert-butylbenzyl)-3-{3,5-di-tert^utylbenzyl)-4,5-diphenylimidazolidin- 2-imine hydrobromide White foam; 98% yield; [α]? = - 125.3 (c 1.37, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 9.29 (s, 2H), 7.37-7.23 (m, 8H), 6.97 (d, J = 1.6 Hz, 4H), 6.95- 6.89 (m, 4H), 5.76 (d, J - 15.0 Hz, 2H), 4.25 (s, 2H), 3.89 (d, J = 14.9 Hz, 2H), 1.26 (s, 36H); 13C NMR (100 MHz, CDCI3): δ = 156.35, 151.24, 137.16, 132.47, 129.24, 129.17, 126.92, 123.37, 122.03, 68.24, 49.25, 34.74, 31.40; IR: 3423, 2964, 1662, 1600, 1363, 1265, 1201 , 734, 700 cm"1; HRMS (ESI) calcd for C45H6oBr 3 m/z [M-Br- ]+: 642.4787; found: 642.4781. (4S,5S)-1,3-bis(3,5-di-tert-butyl-2-ch]orobenzyl)-4,5-diphenylimidazolidin-2-imine hydrobromide White solid; 78% yield; mp: 167.1-168.8 °C; [α]? = -44.9 (c 2.6, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 9.19 (s, 2H), 7.35 (d, J = 2.3 Hz, 2H), 7.33 - 7.20 (m, 8H), 6.98 (d, J = 6.9 Hz, 4H), 5.89 (d, J = 14.6 Hz, 2H), 4.15 (d, J = 14.7 Hz, 2H), 3.96 (s, 2H), 1.52 (s, 18H), 1.10 (s, 18H); 3C NMR (100 MHz, CDCI3): δ = 156.32, 148.71 , 146.73, 137.57, 131.53, 131.16, 129.15, 128.98, 128.09, 127.07, 125.37, 68.73, 49.69, 36.62, 34.41, 31.03, 29.81 ; IR: 3396, 3053, 2966, 2358, 1666, 1558, 1363, 1124, 1037 cm"1; HRMS (ESI) calcd for C45H58BrCI2N3 m/z [M-Br-] +: 710.4008; found: 710.3995. (4S,5S)-1 -(2-bromo-3,4-di-tert-butylbenzyl)-3-(2-bromo-3,5-di-tert-butylbenzyl)-4,5- diphenylimtdazolidin-2-imine hydrobromide White hygroscopic foam; 87% yield; [a]JF = -96.2 (c 0.42, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 9.26 (s, 2H), 7.34 (d, J = 2.3 Hz, 2H), 7.32-7.23 (m, 6H), 7.02 (d, J = 6.7 Hz, 4H), 6.44 (d, J = 2.3 Hz, 2H), 5.92 (d, J = 14.5 Hz, 2H), 4.25 (d, J = 14.6 Hz, 2H), 3.93 (s, 2H), 1.55 (s,18H), 1.06 (s, 18H); 3C NMR (100 MHz, CDCI3): δ = 156.34, 149.25, 148.25, 137.61 , 133.28, 129.16, 128.92, 128.61 , 127.07, 125.72, 122.20, 68.73, 52.28, 37.37, 34.37, 30.93, 29.99; IR: 3257, 2966, 1660, 1562, 1456, 1427, 1396, 1016, 883 cm"1; HRMS (ESI) calcd for
Figure imgf000023_0001
m/z [M-Br-] +: 801.2817; found: 801.2822. (4S,5S)-1,3-bis(3,5-di-tert-butyl-2-iodobenzyl)-4,5-diphenylimidazolidin-2-imine
hydrobromide Pale yellow foam; >99% yield; [a]g = -89.3 (c 1.36, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 9.23 (s, 2H), 7.36 - 7.16 (m, 8H), 7.07 (dd, J = 11.4, 5.7 Hz, 4H), 6.43 (d, J = 2.1 Hz, 2H), 5.72 (d, J = 14.5 Hz, 2H), 4.53 (d, J = 14.6 Hz, 2H), 3.95 (s, 2H), 1.53 (s, 18H), 1.03 (s, 18H); 13C NMR (100 MHz, CDCI3): δ = 156.90, 151.12, 150.04, 137.66, 136.69, 129.14, 128.80, 127.96, 127.03, 125.29, 98.85, 69.14, 57.09, 37.85, 34.31 , 30.88, 30.33; IR: 3325, 3188, 3034, 2964, 2872, 1651 , 1556, 1396, 1363, 1234, 1199, 1149, 11 19, 1001 , 734 cm"1; HRMS (ESI) calcd for C45H58Brl2N3 m/z [M-Br-] +: 894.2720; found: 894.2723. (4S,5S)-2-({(4SI5S)-1,3-bis(3,5-di4ert-butylbenzyl) 5-diphenylimidazolidin-2- ylidene)amino)-1,3-bis(3,5-di-tert-butylbenzy[)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3- ium chloride(la) Brown foam; 53% yield; [α]£ = -89.0 (c 1.05, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.38 (t, J = 7.4 Hz, 4H), 7.33-7.24 (m, 12H), 6.92-6.88 (m, 8H), 6.86 (d, J - 1.6 Hz, 8H), 5.20 (d, J = 14.8 Hz, 4H), 4.40 (s, 4H), 4.1 1 (d, J = 14.8 Hz, 4H), 1.11 (s, 72H); 13C NMR (100 MHz, CDCI3): δ = 157.24, 151.99, 136.27, 131.53, 129.78, 129.51 , 127.13, 123.17, 122.39, 68.04, 49.17, 34.66, 31.15; IR: 2964, 2868, 1600, 1456, 1363, 1201, 1139, 945, 734, 698 cm"1; HRMS (ESi) calcd for Ο90Η116ΟΙΝ5 m/z [M-CI-] +: 1266.9231 ; found: 1266.9229.
(4S,5S)-2-(((4S,5S)-1,3^is(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenyhmidazolidin-2- yIidene)amino)-1,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenyl-4,5-dihydro-1 H- imidazol- 3-ium chloride(lb) Pale yellow powder; 71 % yield; mp: 178.5-180.3 °C; [ ]^ = +5.3 (c 1.14, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.37 (d, J = 2.1 Hz, 4H), 7.33 - 7.27 (m, 1 H), 7.21 (t, J = 7.5 Hz, 8H), 6.94 (d, J = 7.3 Hz, 8H), 6.78 (d, J = 2.1 Hz, 1 H), 5.02 (d, J = 14.4 Hz, 4H), 4.62 (d, J = 14.4 Hz, 4H), 4.36 <s, 4H), 1.45 (s, 36H), 1.09 (s, 36H); 3C NMR (100 MHz, CDC 13): δ = 157.93, 149.50, 147.08, 136.38, 131.21 , 130.36, 129.46, 129.34, 127.07, 126.45, 125.92, 70.01 , 49.30, 36.63, 34.55, 31.06, 29.73; IR: 2966, 2872, 1622, 1485, 1365, 1037, 947 cm"1; HRMS (ESI) calcd for C90H112CI5N5 m/z [M-CI-] +: 1402.7672; found: 1402.7646. (4S,5S)-2-(((45,5S)-1 ,3-bis{2-bromo-3,5-di-tert-butyIbenzyl)-4,5 diphenylimidazolidin-2- ylidene)arnino)-1,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-4,5-diphenyl-4,5-dihydro-1H- imidazol-3-ium chloride (1c) Beige powder; 78% yield; mp:200.1-200.5 °C; [a¾f = + 14.4 (c 1.43, CHCI3); 1H NMR (400 MHz, CDCI3): δ = 7.36 (d, J = 2.1 Hz, 4H), 7.29 (d, J = 7.4 Hz, 4H), 7.21 (t, J = 7.4 Hz, 8H), 6.96 (d, J = 7.3 Hz, 8H), 6.80 (d, J = 2.1 Hz, 4H), 5.00 (d, J = 14.4 Hz, 4H), 4.74 (d, J ~ 14.4 Hz, 4H), 4.41 (s, 4H), 1.48 (s, 36H), 1.07 (s, 36H); 13C NMR (100 MHz, CDCI3): δ = 158.19, 150.05, 148.52, 136.21 , 132.95, 129.38, 129.31 , 127.10, 126.65, 126.19, 121.46, 77.32, 52.22, 37.39, 34.55, 31.01 , 29.91 , 17.41 ; IR: 2966, 1622, 1423, 1365, 1018 cm"1; HRMS (ESI) calcd for
Figure imgf000024_0001
m/z [M-CI-J+: 1582.5610; found: 1582.5624.
Figure imgf000024_0002
(4S,5S)-2-{((4S,5S)-1,3-bis(3,5-di-tert-butyl-2- iodobenzyl)-4,5-diphenylimidazolidin-2- yIidene)amino)-1,3-bis(3,5-di-tert-butyl-2- iodobenzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-lum chloride (1d) Brown powder; 27% yield; mp:195.2- 196.7 eC; [α]? = -9.4 (c 0.35, CHCl3); 1H NMR (400 MHz, CDCI3): δ = 7.32 (d, J = 2.2 Hz, 4H), 7.28 (d, J - 7.4 Hz, 4H), 7.22 (t, J = 7.4 Hz, 8H), 6.99 (d, J = 7.3 Hz, 8H), 6.76 (d, J = 2.1 Hz, 4H), 5.04 (d, J = 14.4 Hz, 4H), 4.87 (d, J = 14.4 Hz, 4H), 4.48 (s, 4H), 1.55 (d, 36H), 1.03 (s, 36H); 13C NMR (100 MHz, CDCI3): δ = 158.23, 151.64, 150.91 , 136.17, 136.02, 129.46, 129.40, 127.11 , 126.01 , 125.86, 98.62, 70.45, 57.99, 38.00, 34.50, 30.99, 30.32; IR: 2964, 2870, 1651 , 1556, 1504, 1454, 1361, 1201 , 1165, 1001 , 731 cm"1; HRMS (ESI) calcd for C9oH112CII4N5 /z [M-CI-] +: 1770.5097; found: 1770.5073.
Preparation 4
Syntheses and Characterization of Sulfinyl Precursors Preparation of heteroaromatic thiols
Benzo[b]thiophene-2-thiol and 3-methylbenzo[b]thiophene-2-thiol ((a) K. Hirai, K. Bessho, T. Kitagawa, H. Tomioka, J. Phys. Org. Chem. 2010, 23, 347-356; (b) D. Sperandio, H. J. Hansen, Helv. Chim. Acta 1995, 78, 765-771 ), 3-methyl-thiophene-2 -thiol, 5- methy!thiophene-2-thiol and 3,5-dimethylthiophene-2-thiol (B. H.Zhong. et al. Acyclic nucleoside phosphonate derivative and its pharmaceutical use. Faming ZhuaniiShenqing, 101293899, 29 Oct 2008), furan-2-thiol and benzofuran-2-thiol (J. A. Wiles, A. S. Phadke, B. J. Bradbury, W. J. Pucci, J. A. Thanassi, M. Deshpande, J. Med. Chem. 2011 , 54, 3418- 3425.) were prepared according to the literature procedures and used directly in next steps without further purifications. Preparation of sulfanyl precursors Sulfanyl precursors were prepared according to the literature procedures (Method A, B or C) and used directly in next steps without further purifications. Preparation 4a
General procedure for Michael addition of electron-deficient olefins with thiols
Figure imgf000025_0001
9a
EWG = C02Me, CCfcEt, C02fBu,
C02Ph, SOzPh, CN
See, for example a) R. K. Haynes, S. C. Vonwiller, J, P. Stokes, L M. Mer!ino, Aust. J. Chem. 1988, 41 , 881- 895; b) C. Caupene, C. Boudou, S. Perrio, P. Metzner, J. Org. Chem. 2005, 70, 2812-2815; c) F. Gelat, J. Jayashankaran, J. F. Lohier, A. C. Gaumont, S. Perrio, Org. Lett. 2011 , 13, 3170-3173; d) Q. P. G. R. D. HUANG, 10555 Science Center DriveSan Diego, California, 92121 , US), RUi, Eugene, Yuanjin (Pfizer Global Research & Development, 10555 Science Center DriveSan Diego, California, 92121, US), PFIZER INC. (235 East 42nd Street, New York, New York, 10017, US), HUANG, Qinhua (Pfizer Global Research & Development, 10555 Science Center DriveSan Diego, California, 92121 , US), RUI, Eugene, Yuanjin (Pfizer Global Research & Development, 10555 Science Center DriveSan Diego, California, 92121 , US), 2009. Et3N (5 mol %) was added to a solution of thiol (0.5mmol) and electron-deficient olefin 9a (0.5 mmol) in THF (0.1 mL) at 0 oC. The resulting reaction mixture was stirred for appropriate time at room temperature (monitored by TLC). After removing solvent under reduced pressure, the crude residue was used in next step without further purification. Preparation 4b (N. Furukawa, F. Takahashi, T. Kawai, K. Kishimoto, S. Ogawa, S. Oae, Phosphorous and Sulfur and the Related Elements 1983, 16, 167-180.)
Figure imgf000026_0001
reflux Methyl 3-bromopropanoate 9b (133 pL, 1.2 mmol, 1.2 equiv) was added dropwise to a solution of 2-mercaptopyridine (111 mg, 1 mmol, 1.0 equiv) and Et3N (209 pL, 1.5 mmol, 1.5 equiv) in CH3CN (0.2 mL) at room temperature. Then the mixture was stirred for 24 h at 82 oC. After the removal of solvent under reduced procure, the resulting residue was purified by flash chromatography to afford the desired compound as pale yellow oil in 76% yield. 1H NMR (400 MHz, CDCI3): δ = 8.42 (d, J = 4.2 Hz, 1 H), 7.49 (td, J = 7.8, 1.8 Hz, 1 H), 7.17 (d, J = 8.1 Hz, 1 H), 6.99 (ddd, J = 7.2, 5.0, 0.7 Hz, 1H), 3.69 (s, 3H), 3.44 (t, J * 7.1 Hz, 2H), 2.79 (t, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCI3): δ = 172.46, 158.05, 149.09, 136.24, 122.52, 1 19.53, 51.73, 34.42, 25.01 ; IR: 2951 , 1732, 1579, 1556, 1454, 1415, 1249, 1124, 985, 759 cm"1; HRMS (ESI) calcd for CgHnN02S m/z [M+H] +: 198.0589; found: 198.0589.
Preparation 4c (N. Furukawa, F. Takahashi, T. Kawai, K. Kishimoto, S. Ogawa, S. Oae, Phosphorous and Sulfur and the Related Elements 1983, 16, 167-180.)
Figure imgf000027_0001
reflux
Methyl 3-bromopropanoate 9b (1.37 mL, 12.5 mmol, 1 .2 equiv.) was added dropwise to a solution of 5-methoxy-1-methyl-1 H-benzo[d]imidazole-2-thiol (2.03 g, 10.4 mmol, 1.0 equiv.) in MeOH (10 mL) at room temperature. Then the mixture was stirred for 24 h at 82 oC. After the removal of solvent under reduced procure, the resulting residue was purified by flash chromatography to afford the desired compound as a red solid in quantitative yield. 1H NMR (400 MHz, CDCI3): 5 = 7.16 (d, J = 2.3 Hz, 1 H), 7.09 (d, J = 8.7 Hz, 1 H), 6.84 (dd, J = 8.7, 2.4 Hz, 1 H), 3.83 (s, 3H), 3.69 (s, 3H), 3.61 (s, 3H), 3.57 (t, J = 6.8 Hz, 2H), 2.90 (t, J - 6.8 Hz, 2H); 13C NMR (100 MHz, CDCI3): δ = 172.12, 155.92, 151.06, 144.03, 131.39, 1 11.37, 108.70, 101.09, 55.75, 51 .74, 34.41 , 29.98, 27.22; IR: 1732, 1647 cm"1; HRMS (ESI) calcd for C13H16N203S m/z [M+H] +: 281.0960; found: 281.0955.
Preparation 5
Preparation of sulfinyl precursors
Figure imgf000027_0002
EWG C02 e, C02Et,C02 iBu,
C02Ph, S02Ph, CN
General procedure for sulfides oxidation to sulfoxides To a 2 M solution of sulfide (1 mmol) in 2, 2, 2-trifluoroethanol (TFE) (1.0 mL) at 0 CC, H202 (35% wt in water, 160 μΐ, 1.8 mmol, 1.8 equiv) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for appropriate time (monitor by TLC). Solid sodium sulfite (1.8 mmol, 1.8 equiv) was added then the reaction mixture was stirred for 30 min. The resulting mixture was filtered on ceiite, dried over MgS04, filtered and evaporated under reduced pressure. The crude product was then purified by column chromatography on silica gel to afford the pure anticipated sulfoxide 2a-f, 4a-e and 5b-f. For the sulfide oxidation to sulfoxide 5a, additional ammonium molybdate tetrahydrate (5 mo! %) was added as a catalyst to promote this transformation.
Methyl 3-(thiophen-2-yisulfinyl)propanoate(2a) Colourless oil; 93% yield; 1H NMR (400 MHz, CDCI3): 6 = 7.80-7.73 (m, 1 H), 7.52 (dd, J = 5.1 , 3.0 Hz, 1 H), 7.22 (dd, J = 5.1 , 1.0 Hz, 1 H), 3.68 (S, 3H), 3.26 (ddd, J = 13.5, 8.2, 7.0 Hz, 1 H), 3.15-3.03 (m, 1 H), 2.89-2.76 (m, 1 H), 2.62 (ddd, J = 17.3, 8.2, 6.1 Hz, 1 H); 13C NMR (100 MHz, CDCI3): 5 = 171.58, 142.35, 128.63, 126.26, 122.80, 52.15, 50.50, 26.08; IR: 1732, 1436, 1406, 1359, 1224, 1176, 1041 cm"1; HRMS (ESI) calcd for ¾Η10Ο352 /z [M+H]+: 219.0150; found: 219.0147. Ethyl 3-(thiophen-2-ylsulfinyl)propanoate(2b) Colourless oil; 83% yield; 1H NMR (400 MHz, CDCI3): δ = 7.66 (dd, J = 5.0, 0.7 Hz, 1 H), 7.46 (dd, J = 3.6, 0.8 Hz, 1H), 7.13 (dd, J = 4.7, 3.9 Hz, 1 H), 4.14 (q, J = 7.1 Hz, 2H), 3.37 - 3.17 (m, 2H), 2.81 (dt, J = 17.2, 7.5 Hz, 1 H), 2.73 - 2.53 (m, 1 H), 1.25 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 170.82, 145.05, 131.17, 129.67, 127.48, 61.18, 52.59, 26.99, 14.08; IR: 2981 , 1732, 1373, 1234, 1043, 850, 719 cm"1; HRMS (ESI) calcd for
Figure imgf000028_0001
m/z [M+H] +: 233.0306; found: 233.0305. tert-butyl 3-(thiophen-2-ylsulfinyl)propanoate{2c) Colourless oil; 82% yield; H NMR (400 MHz, CDCIa): δ = 7.65 (dd, J = 5.0, 1.1 Hz, 1 H), 7.46 (dd, J = 3.6, 1.1 Hz, 1 H), 7.13 (dd, J = 4.9, 3.7 Hz, 1 H), 3.24 (t, J = 7.3 Hz, 2H), 2.73 (dt, J = 17.2, 7.5 Hz, 1 H), 2.57 (dt, J = 17.2, 7.2 Hz, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCI3): δ = 169.99, 145.31 , 131.06, 129.57, 127.46, 81.64, 52.93, 28.16, 27.99; IR: 2978, 1730, 1367, 1247, 1155, 1043, 848, 725 cm"1; HRMS (ESI) calcd for CnHu jSa m/z [M+H] +: 261.0619; found: 261.0627. phenyl 3-(thiophen-2-ylsulfinyl)propanoate{2d) Colourless oil; 74% yield; 1H NMR (400 MHz, CDCI3): δ = 7.69 (d, J = 4.9 Hz, 1 H), 7.51 d, J = 3.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.24 (dd, J = 12.4, 4.8 Hz, 1 H), 7.19-7.12 (m, 1 H), 7.07 (d, J = 8.0 Hz, 2H), 3.49-3.25 (m, 2H), 3.19-3.04 (m, 1 H), 3.01-2.86 (m, 1 H); 13C NMR (100 MHz, CDC!3): δ = 169.53, 150.38, 144.90, 131.26, 129.67, 129.44, 127.60, 126.06, 121.28, 52.31 , 27.05; IR: 3088, 1755, 1591 , 1492, 1401 , 1195, 1165, 1043, 850, 745, 719 cm"1; HRMS (ESI) calcd for Ci3Hi203S2 m/z [M+H] +: 281.0306; found: 281.0300.
2-((2-(phenylsulfonyl)ethyl)sulfinyl)thiophene(2e) White solid; 82% yield; mp:121.9- 122.7 °C; 1H NMR (400 MHz, CDCI3): δ = 7.95-7,84 (m, 2H), 7.69 (dt, J = 4.9, 4.2 Hz, 2H), 7.59 (t, J = 7.7 Hz, 2H), 7.43 (dd, J = 3.7, 1.1 Hz, 1 H), 7.15 (dd, J = 4.9, 3.8 Hz, 1 H), 3.57- 3.46 (m, 1H), 3.40 (ddd, J = 14.1 , 8.5, 2.9 Hz, 1 H), 3.36- 3.30 (m, 1 H), 3.29-3.19 (m, 1 H); 13C NMR (100 MHz, CDCI3): δ = 143.83, 138.46, 134.30, 131.68, 129.74, 129.58, 128.05, 127.81 , 49.53, 48.82; IR: cm"1; IR: 2304, 1446, 1421 , 1323, 151, 1051 cm"1; HRMS (ESI) calcd for C12H1203S3 /z [M+H] +: 301 .0027; found: 301.0042.
3-(thiophen-2-ylsulfinyl)propanenitrile{2f) Colourless oil; 90% yield; H NMR (400 MHz, CDCI3): δ = 7.71 (dd, J = 5.0, 1.2 Hz, 1H), 7.50 (dd, J = 3.7, 1.2 Hz, 1 H), 7.17 (dd, J = 5.0, 3.7 Hz, 1 H), 3.35 - 3.12 (m, 2H), 2.89 (ddd, J = 17.3, 8.1 , 7.0 Hz, 1 H), 2.69 (ddd, J = 17.3, 8.4, 6.1 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 143.22, 131.91 , 130.13, 127.86, 116.87, 51.81 , 10.51 ; IR: 2241 , 1647, 1236, 1035, 854, 715 cm"1; HRMS (ESI) calcd for C7H7NOS2 m/z [M+H] +: 186.0047; found: 186.0044. Methyl 3-((3-methylthiophen-2-yl)sulfinyl)propanoate(4a) Orange oil; 62% yield; 1H NMR (300 MHz, CDCI3): 6 = 7.56 (d, J = 5.0 Hz, 1H), 6.90 (d, J = 5.0 Hz, 1H), 3.70 (s, 3H), 3.47 - 3.04 (m, 2H), 2.95 - 2.54 (m, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 171.36, 141.49, 138.84, 130.46, 130.39, 52.19, 51.67, 27.20, 14.40; IR: 3099, 2953, 1732, 1436, 1361 , 1238, 1176, 1045, 829 cm'1; HRMS (ESI) calcd for C9H1203S2 m/z [M+H] +: 233.0306; found: 233.0303.
Methyt 3-{(5-methylthiophen-2-yl)sulfinyl)propanoate(4b) Colourless oil; 87% yield; 1H NMR (400 MHz, CDCI3): δ = 7.29 (d, J = 3.6 Hz, 1 H), 6.80-6.70 (m, 1H), 3.70 (s, 3H), 3.37- 3.17 (m, 2H), 2.88-2.73 (m, 1 H), 2.73-2.58 (m, 1 H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCI3): 5 = 171.34, 147.28, 141.30, 130.93, 125.71, 52.16, 52.14, 27.08, 15.81 ; IR: 2953, 1737, 1732, 1440, 1359, 1222, 1176, 1041, 977, 808 cm'1; HRMS (ESI) calcd for C9H1203S2 m/z [M+H] +: 233.0306; found: 233.0305.
Methyl 3-((3,5-dimethylthiophen-2-yl)sulfinyl)propanoate(4c) Colourless oil; 53% yield; 1H NMR (400 MHz, CDCI3): δ = 6.58 (s, 1 H), 3.71 (s, 3H), 3.45 - 3.31 (m, 1 H), 3.23 (dt, J = 13.1 , 7.5 Hz, 1H), 2.87 - 2.66 (m, 2H), 2.50 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCI3): δ - 171.36. 145.93, 142.64, 135.50, 128.89, 52.12, 51.55, 27.51 , 15.80, 14.41 ; IR: 2953, 2924, 1732, 1552, 1435, 1359, 1236, 1138, 1056, 1033, 831 cm"1; HRMS (ESI) calcd for C10H14O3S2 /z [M+H] +: 247.0463; found: 247.0462.
Methyl 3-(benzo[b]thiophen-2-ylsu!finyl)propanoate(4d) Colourless oil; 80% yield; 1H NMR (400 MHz, CDCi3): δ = 7.93-7.86 (m, 1 H), 7.86-7.81 (m, H), 7.47-7.38 (m, 2H), 7.26 (s, 1 H), 3.68 (s, 3H), 3.45-3.35 (m, 1 H), 3.35-3.25 (m, 1 H), 2.88 (ddd, J = 17.3, 7.9, 7.1 Hz, 1 H), 2.69 (ddd, J = 17.3, 8.2, 6.1 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 171.31 , 145.52, 141.35, 138.16, 126.62, 126.36, 125.27, 124.89, 122.82, 52.20, 51.93, 26.50; IR: 1737, 1732, 1435, 1359, 1242, 1176, 1051 , 977, 831 cm'1; HRMS (ESI) calcd for Cl2H1203S2 m/z [M+H] +: 269.0306; found: 269.0299. Methyl 3-((3-methylbenzo[b]thiophen-2- yl)sulfinyl)propanoate(4e) Pale yellow oil; 93% yield; 1H NMR (400 MHz, CDCI3): δ = 7.92-7.85 (m, 1 H), 7.82-7.71 (m, 1 H), 7.51-7.39 (m, 2H), 3.68 (s, 3H), 3.42 (ddd, J = 13.9, 7.5, 6.4 Hz, 1 H), 3.31 (dt, J = 13.2, 7.4 Hz, 1 H), 2.86 (dt, J ~ 17.4, 7.4 Hz, 1 H), 2.74 (ddd, J = 17.4, 7.6, 6.5 Hz, 1 H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 171.28, 140.43, 140.34, 139.37, 135.98, 126.61 , 124.85, 123.06, 122.89, 52.19, 51.53, 27.18, 12.73; IR: 3055, 2953, 1737, 1517, 1438, 1319, 1105, 1047, 979, 731 cm"1; HRMS (ESI) calcd for C13H1403S2 m/z [M+H] +: 283.0463; found: 283.0457. Methyl 3-((5-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)sulfinyl)propanoate(5a)
Reddish oil; 84% yield; 1H NMR (400 MHz, CDCI3): δ - 7.30 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1 H), 7.05 (dd, J = 8.9, 2.4 Hz, 1 H), 4.08 (s, 3H), 3.86 (s, 3H), 3.82-3.70 (m, 2H), 3.66 (s, 3H), 3.00 (m, 1H), 2.92-2.81 (m, 1 H); 13C NMR (100 MHz, CDCI3): 6 = 171.38, 157.01 , 150.16, 142.73, 131.53, 115.81 , 110.35, 101.99, 55.73, 52.17, 47.45, 30.93, 26.49; IR: 1735, 1646, 1614, 1010 cm"1; HRMS (ESI) calcd for C13H16N204S m/z [M+H] +: 297.0909; found: 297.0919.
Methyl 3-((3T5-dimethylphenyl)sulfinyl)propanoate(5b) Colourless oil; quantitative yield; 1H NMR (400 MHz, CDCI3): δ = 7.20 (s, 1 H), 7.1 1 (s, OH), 3.67 (s, 3H), 3.20 (ddd, J = 13.1 , 8.7, 6.5 Hz, 1 H), 3.01 - 2.76 (m, 2H), 2.55 (ddd, J = 17.0, 8.7, 5.5 Hz, 1 H), 2.38 (s, 6H); 13C NMR (100 MHz, CDCI3): δ = 171.76, 142.70, 139.33, 132.91 , 121.44, 52.06, 51.11, 26.12, 21.27; IR: 2953, 1730, 1606, 1436 ,1359, 1238, 1 174, 1049, 852, 686 cm"1; HRMS (ESi) calcd for Cl2H1603S m/z [M+H] +: 241.0898; found: 241.0901. Methyl 3-(furan-2-ylsulfinyl)propanoate(5c) Colourless oil; 85% yield; 1H NMR (400 MHz, CDCI3): δ = 7.69-7.62 (m, 1 H), 6.97 (dd, J = 3.5, 0.6 Hz, 1 H). 6.52 (dd, J = 3.4, 1.8 Hz, 1 H), 3.69 (s, 3H), 3.44 (dd, J = 7.8, 6.4 Hz, 1 H), 3.38 (dd, J = 7.7, 7.2 Hz, 1 H), 2.79 (t, J = 7.5 Hz, 1H), 2.71 (dd, J = 7.8, 6.5 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 171.27, 151.07, 146.99, 116.40, 111.40, 52.13, 47.09, 26.61 ; IR: 3128, 2954, 1737, 1732, 1438, 1365, 1242, 1128, 1041 , 1010, 908, 763 cm'1; HRMS (ESI) calcd for C8Hi0O4S m/z [M+H] +: 203.0378; found: 203.0375.
Methyl 3-((2-methylfuran-3-yl)sulfinyl)propanoate(5d) Orange oil; 71 % yield; 1H NMR (400 MHz, CDCi3): δ = 7.40 (d, J = 2.0 Hz, 1 H), 6.66 (d, J = 2.0 Hz, 1H), 3.70 (s, 3H), 3.35- 3.20 (m, 1 H), 3.19-3.04 (m, 1H), 2.84-2.61 (m, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 171.40, 154.75, 142.64, 121.67, 106.60, 52.16, 49.51 , 27.38, 12.38; IR: 2954, 1732, 1585, 1517, 1438, 1361 , 1232, 1128, 1039, 1012, 889, 744 cm"¾; HRMS (ESi) calcd for C9H1204S m/z [M+H] +: 217.0535; found: 217.0529.
Methyl 3-{benzofuran-2-ylsulfinyl)propanoate(5e) Pale yellow oil; 78% yield; H NMR (400 MHz, CDCI3): δ = 7.67 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 8.3 Hz, 1 H), 7.47 - 7.38 (m, 1H), 7.37 - 7.29 (m, 2H), 3.67 (s, 3H), 3.50 (t, J = 7.3 Hz, 2H), 2.90 (dt, J = 17.4, 7.4 Hz, 1 H), 2.72 (dt, J = 17.4, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 171 ,30, 156.58, 153.62, 126.95, 126.48, 123.98, 122.31 , 112.23, 112.06, 52.21 , 47.22, 26.20; IR: 2953, 1732, 1444, 1359, 1236, 1168, 1053, 921, 827, 752 cm"1; HRMS (ESI) calcd for C12H1204S m/z [M+H] +: 253.0535; found: 253.0538.
Methyl 3-(pyridin-2-ylsulfiny!)propanoate(5f) Pale yellow oil; 78% yield; 1H NMR (400 MHz, CDCI3): δ = 8.62 (d, J = 4.5 Hz, 1 H), 8.00-7.86 (m, 2H), 7.38 (ddd, J = 6.9, 4.7, 1.7 Hz, 1 H), 3.64 (s, 3H), 3.49 (ddd, J = 13.7, 9.2, 6.1 Hz, 1 H), 3.19 (ddd, J - 13.7, 9.1 , 5.9 Hz, 1 H), 2.85 (ddd, J = 17.0, 9.1 , 6.1 Hz, 1H), 2.44 (ddd, J = 17.0, 9.2, 5.9 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 171.52, 163.72, 149.77, 137.86, 124.66, 120.24, 52.04, 47.94, 25.47; IR: 1737, 1732, 1423, 1361 , 1242, 1178, 1035, 829, 773 cm"1; HRMS (ESI) calcd for C9HN03S m/z [M+H] +: 214.0538; found: 214.0546.
Example 2
Thienyl group is a heterocyclic aromatic ring that can be used as a bioisostere of a phenyl group in order to either improve efficacy or change specificity of binding in medicinal chemistry. Some examples of commercially available drugs containing such a moiety are provided in Figure 1. initially, β-sulfinyl methyl ester 2a was chosen as the model substrate for reaction parameters screening (Table 1 and 2).
Base: The choice of base is crucial to this transformation (Table 1 ). One equivalent base was not efficient to promote the generation of su!fenate anion via retro-Michael reaction. 20 equivalent of CsOH base was chose in term of reaction rate and enantioselectivity which led a slightly improvement than 10 equivalent of that. Moreover, bases with less basicity such as NaOH, KOH, and RbOH usually cannot furnish the completion of reaction and low yield of sulfoxide was observed. On the other hand, in the presence of strong base NaO'Bu as well as KO'Bu, the reaction was too fast and most of the generated sulfenate anion intermediate underwent alkaline hydrolysis without trapping by the benzyl bromide electrophile. Therefore, the yield of desired sulfoxide product was still low.
Precursors and catalytst: The influence of the sulfenate anion precursors 2a-2f activated by different electron-withdrawing group (EWG) was first examined using catalyst 1 a bearing bulky benzyl groups on nitrogen (Table 2). The β-sulfinyl methyl ester 2a (EWG = C02Me) was found to be the appropriate precursor in terms of reactivity and enantioselectivity (Table 2, entry 1 ). Attempts to use other bulkier β-sulfinyl esters did not lead to any improvements (entries 2-4). In particular, β-sulfinyl tert-butyl ester 2c (EWG = C02tBu) was mostly recovered without undergoing the reaction. Both β-sulfinyl sulfone 2e (entry 5, EWG = S02Ph) and β-sulfinyl nitrile 2f (entry 6, EWG = CN) did not lead to better results. Overall, only moderate results were obtained by using pentanidium 1a as catalyst. Further structural modification of pentanidium by the addition of halogens to ortho-position of the benzyl groups led to an increase in enantioselectivity relative to the parent catalyst 1a (entries 7-10). Eventually, it was found that iodinated pentanidium 1 d is the best catalyst, providing sulfoxide 3a with excellent enantioselectivity (91 % ee). These results indicate a stereocontrol enhancement induced by halogenated pentanidiums in comparison with non-halogenated pentanidium 1a.
Figure imgf000033_0001
CQ (h) (%)*
1 CsOH'H2O(10 equiv) toluene -20 12 100 26
2 50% RbOH (10 equiv) toluene -20 12 100 29
3 50% CsOH (10 equiv) toluene -20 2 100 37
4 50% CsOH (10 equiv) toluene -30 10 100 42
5 50% CsOH (10 equiv) toluene -40 12 100 42
6 50% CsOH (20 equiv) toluene -40 12 100 43
7 67% CsOH (10 equiv) toluene -40 12 100 45
8 50% CsOH (10 equiv) toluene -60 48 80 54
9 50% CsOH (20 equiv) toluene -60 48 80 58
10 67% CsOH (20 equiv) toluene -60 48 100 59
1 1 67% CsOH (20 equiv) hexane -60 48 100 23
12 67% CsOH (20 equiv) pentane -60 48 100 37
13 67% CsOH (20 equiv) DCM -60 48 90 0
14 67% CsOH (20 equiv) MTBE -60 48 100 60
15 67% CsOH (20 equiv) CPME -60 48 100 61
16 67% CsOH (20 equiv) CPME -80 120 100 67
17 50% NaOH (20 equiv) CPME -60 48 50 37
18 50% KOH (20 equiv) CPME -60 48 80 61
19 50% RbOH (20 equiv) CPME -60 48 80 60
20 KO¾u (10 equiv) CPME -60 10 100 15^
21 NaO'Bu (10 equiv) CPME -60 10 100 35d
Table 1 laJ [a] Reactions were performed by using 2a (0.02 mmol), and benzyl bromide (0.024 mmol) in the presence of 1 mol % of pentanidium 1a in solvent (0.4 mL). [b] Conversion was determined by TLC. [c] Determined by HPLC analysis using Chiralcel OD-H column, [d] The isolated yield of product 3a is very low. MTBE = Methyl tert-butyl ether. CPME = Cyclopentyl methyl ether.
Figure imgf000034_0001
Entry Catalyst 2 [EWG] Yield ee
1 la 2a [C02Me] 76 61
2 la 2b [C02Et] 39 61
3 la 2c [CC-2/Bu] trace 45
4 la 2d [C02Ph] 39 58
5 la 2e [S02Ph] 29 37
6 la 2f [CN] 73 57
7 lb 2a [COjMe] 67 79
8 lc 2a [C02Me] 72 81
lc 2a [C02Me] 86 88
10M Id 2a [C02Me] 72 91
Table 2la]
[a] Reactions were performed by using 2 (0,02 mmoi) and benzyl bromide (0.024 mmol) in the presence of 1 moi % of pentanidiums with 67 wt% aqueous CsOH solution(45 cL) in CPME (0.4 mL). [b] Yield of the isolated product, [c] Determined by HPLC analysis, [d] The reaction was conducted at -70 °C with saturated CsOH solution (24 L) in a solvent mixture of CPME (0.2 mL)/EtO (0.6 mL).
Reference Example 1 in contrast, commercially available phase-transfer catalysts were also tested and low enantioselectivity was obtained (below 15% ee, Table 3).
Figure imgf000035_0001
(RMS
Maruoka catalyst
entry base solvent temperature time yield (%)["] ee
O (fa)
33% NaOH Toluene/CH2Cb rt 1.5 73 15
(10 equiv.) (7:3)(0.25 mL)
2w 67% CsOH CPME(0.4 mL) rt 0.5 82 10
(10 equiv.)
saturated CsOH CPME(0.4 mL) -60 28 86 9
(20 equiv.)
33% NaOH Toluene/CH2Cl2 rt 12 45 1
(7:3)(0.25 mL)
[f] 33% NaOH Toluene(0.25 mL) rt 12 9 3
(10 equiv.)
67% CsOH CPME(0.4 mL) rt 2 50 3
(10 equiv.)
7M 67% CsOH CPME(0.4 mL) -60 48 70 1
(20 equiv.)
Table 3[a}
[a] Reactions were performed by using 2a (0.02 mmol), and benzyl bromide (0.024 mmol) in the presence of 10 mol % of phase-transfer catalysts, [b] Isolated yield, [c] Determined by HPLC analysis using Chiralcel OD-H column, [d] The reaction was performed under the condition mentioned in reference 7c.[ej Cinchonidinium salt 1f was used as the phase- transfer catalyst, [f] Commercially available Maruoka Catalyst 1g was used as the phase- transfer catalyst.
Example 2
Experimental Procedures for Asymmetric Alkytation of Sulfenate Anions and Characterization of Sulfoxide Products Representative procedure for pentanidium 1d catalysed asymmetric alkylation of in situ generated sulfenate anions
A 5 mL RBF was charged with a solution of methyl 3-(thiophen-2-ylsulfinyi)propanoate 2a (13.1 mg, 0.06 mmol, 1.0 equiv.), benzyl bromide (8.6 pL, 0.072 mmol, 1.2 equiv.) and pentanidium 1d (1.1 mg, 0.0006 mmol, 1 mol %) in a solvent mixture of CPME (0.6 mL) and Et20 (1.8 mL). The reaction mixture was stirred at -70 °C for 30 min, and then saturated CsOH solution (72 μΙ_, 1 ,2 mmol, 20.0 equiv.) was added by syringe in one portion. The reaction mixture was stirred at -70 °C and monitored by TLC. After 2a was completely consumed, reaction was quenched at 0 °C by addition of 1 aqueous HCI solution (1.5 mL) and extracted with CH2CI2 (3 mL * 3). The combined organic layer was washed by brine and dried by Na2S04, filtered and concentrated. The sulfoxide 3a was obtained by flash chromatography (silica gel, hexane-ethyl acetate 10: 1-2:1 ), as colorless oil, 12.3 mg, 87% yield.
Corresponding examples were conducted using the starting materials listed in Table 4, along with the results.
l
Figure imgf000036_0001
sulfenate anion
Entry R Product Time [h] Yield [%]|aJ ee [%f 1
1 PhCH2 3a 12 87 92
2 4-MeC6H4CH2 3b 12 88 94
3 4-CIC6H4CH2 3c 12 84 90[cl
4 4-CF3C6H4CH2 3d 12 83 94[cI
5 3- eOC6H4CH2 3e 12 84 90
6 2-naphthylCH2 3f 12 84 92
7 3g 36 82 92
8 Xx 3h 21 79 92
9 V 3i 21 77 82
10M Me 3j 40 65 77[c]
11 [dI CH3CH2CH2 3k 28 66 81 [c]
12[d] CH3(CH2)eCH2 31 20 69 81 [c]
Tabled
[a] isolated yield, [b] Determined by HPLC analysis, [c] Data was obtained in the present of 1 mol% of pentanidium 1 c. [d] 2.5 equivalent of alkyl iodides was used. The absolute configuration of 3a was assigned to be R by single- crystal X-ray diffraction of 6q and DFT calculated specific optical rotation of 3a and 6q (see Example 4).
Characterisation data for the prepared sulfoxides are provided below. (R)-2-(benzylsulfinyl)thiophene(3a) Colorless oil; 87% yield; H NMR (400 MHz, CDCI3): δ = 7.62 (d, J = 4.8 Hz, 1 H), 7.36 - 7.19 (m, 3H), 7.16 - 6.96 (m, 4H), 4.36 (d, J = 12.4 Hz, 1 H), 4.14 (d, J = 12.4 Hz, 1 H); 3C NMR (100 MHz, CDCI3): δ = 144.94, 130.98, 130.19, 129.66, 129.24, 128.65, 128.42, 127.12, 65.07; IR: 1045 cm"1; HRMS (ESI) calcd for CnH10OS2 m/z [M+H] +: 223.0251 ; found: 223.0255; [a]$ = -86.7 (c 0.85, CHCI3); HPLC analysis: Chiraicel OD-H (Hex/IPA = 90/10, 1.0 mUmin, 230 nm, 22°C), 20.7 (major), 29.1 min, 92% ee. {R)-2-((4-methylbenzyl)sulfinyl)thiophene(3b) Colorless oil. 88% yield; H NMR (400 MHz, CDCI3): 6 = 7.61 (dd, J = 4.9, 1.1 Hz, 1 H), 7.13 (dd, J ~ 3.6, 1.1 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 2H), 7.03 (dd, J = 4.9, 3.7 Hz, 1H), 6.97 (d, J = 7.9 Hz, 2H), 4.32 (d, J = 12.5 Hz, 1 H), 4.11 (d, J = 12.5 Hz, 1 H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 145.16, 138.31 , 130.88, 130.07, 129.66, 129.35, 127.09, 126.13, 64.84, 21.16; IR: 2918, 1907, 1514, 1401 , 1224, 1087, 1045, 1001 cm"1; HRMS (ESI) calcd for C12H12OS2 m/z [M+H] +: 237.0408; found: 237.0418; [a]$ = -106.7 (c 1.06, CHCI3); HPLC analysis: Chiraicel OD-H (Hex/iPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 18.4 (major), 23.7 min, 94% ee.
(R)-2-((4-chlorobenzyl)sulfinyl)thiophene(3c) White solid; 84% yield; mp:96.0-97.5 °C; 1H NMR (400 MHz, CDCI3): δ = 7.63 (dd, J = 5.0, 1.2 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.16 (dd, J = 3.7, 1.2 Hz, 1 H), 7.05 (dd, J = 5.0, 3.7 Hz, 1 H), 7.03 - 6.98 (m, 2H), 4.26 (d, J = 12.6 Hz, 1 H), 4.13 (d, J = 12.6 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 144.53, 134.62, 131.47, 131.17, 129.71 , 128.83, 127.65, 127.23, 64.03; IR: 2972, 1489, 1401 , 1224, 1087, 1045, 1033 cm"1; HRMS (ESI) calcd for C HeCIOSz m/z [M+H] +: 256.9862; found: 256.9875; [a]$ = - 56.9 (c 1.24, CHCI3); HPLC analysis: Chiraicel OD-H (Hex IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 22.1 (major), 30.1 min, 90% ee.
(/?)-2-((4-(trifluoromethyl)benzyJ)sulfinyl)thiophene(3d) White solid; 83% yield; mp: 161.9- 163.1 °C; 1H N R (400 MHz, CDCI3): δ = 7.64 (dd, J = 5.0, 1.2 Hz, 1 H), 7.55 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.18 (dd, J = 3.7, 1.2 Hz, 1 H), 7.06 (dd, J = 4.9, 3.7 Hz, 1 H), 4.32 (d, J = 12.6 Hz, 1 H), 4.22 (d, J = 12.5 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 144.38, 133.23, 131.33, 130.56, 130.49, 129.72, 127.31 , 125.52 (q, J = 3.7 Hz), 122.55, 64.21 ; 19F NMR (376 MHz, CDCI3): δ = -62.70; IR: 3049, 1417, 1126, 1066, 1047, 750 cm"1; HRMS (ESI) calcd for C12H9F3OS2 m/z [M+H] +: 291.0125; found: 291.0115; = -106.5 (c 1.13, CHCI3); HPLC analysis: Chiraicel OD-H (Hex/IPA = 90/10, 1.0 mLmin, 230 nm, 22°C), 28.7 (major), 24.2 min, 93% ee. {/?)-2-((3-methoxybenzyI)sulfinyl)thiophene(3e) Colourless oil; 84% yield; H NMR (400 MHz, CDCI3): 6 = 7.62 (d, J = 5.0 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H), 7.15 (d, J = 3.6 Hz, 1 H), 7.07 - 6.99 (m, 1 H), 6.84 (dd, J = 8.3, 2.4 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1 H), 6.59 (s, 1 H), 4.34 (d, J = 12.4 Hz, 1 H), 4.10 (d, J = 12.4 Hz, 1 H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 159.68, 145.04, 131.00, 130.63, 129.73, 129.65, 127.13, 122.47, 1 15.29, 114.35, 65.18, 55.19; IR: 1600, 1489, 1153, 1041 , 788 cm"1; HRMS (ESI) calcd for C^H-^C^ m/z [M+H] +: 253.0357; found: 253.0356; [a]$ = -91.5 (c 1.07, CHCI3); HPLC analysis: C Chiralcel OD-H (Hex/IPA - 90/10, 1.0 mUmin, 230 nm, 22°C), 25.3 (major), 36.9 min, 90% ee. (/¾)-2-((naphthalen-2-ylmethyI)sulfinyl)thiophene(3f) Beige powder; 84% yield; mp:93.9- 94.8 °C; H NMR (400 MHz, CDCI3): δ = 7.85 - 7.78 (m, 1 H), 7.75 (t, J = 5.4 Hz, 2H), 7.62 (dd, J = 5.0, 1.2 Hz, 1 H), 7.56 (s, 1 H), 7.52 - 7.43 (m, 2H), 7.18 (dd, J = 8.4, 1.6 Hz, 1 H), 7.11 (dd, J = 3.6, 1.2 Hz, 1H), 7.00 (dd, J = 4.9, 3.7 Hz, 1 H), 4.52 (d, J = 12.4 Hz, 1 H), 4.31 (d, J = 12.4 Hz, 1H); 13C NMR (100 MHz, CDCI3): δ = 144.94, 133.17, 132.98, 131.04, 129.76, 129.71 , 128.38, 127.86, 127.67, 127.42, 127.14, 126.69, 126.45, 126.39, 65.36; IR: 2983, 1508, 1419, 1406, 1224, 1045, 821 cm-1; HRMS (ESI) calcd for Ci5Hi2OS2 m/z [M+H] +: 273.0408; found: 273.0410; [«]# = -110.4 (c 1.32, CHCI3); HPLC analysis: Chiralcel OD- H (Hex/IPA = 90/10, 1.0 mUmin, 230 nm, 22°C), 30.5 (major), 41.3 min, 92% ee. (K)-2-(allylsulfinyl)thiophene(3g) Pale yellow oil; 82% yield; H NMR (400 MHz, CDCI3): δ = 7.65 (dd, J = 5.0, 1.2 Hz, 1 H), 7.43 (dd, J = 3.7, 1.2 Hz, 1 H), 7.12 (dd, J = 5.0, 3.7 Hz, 1 H), 5.71 (ddt, J = 17.6, 10.2, 7.5 Hz, 1 H), 5.37 (d, J = 10.2 Hz, 1 H), 5.29 (dd, J = 17.0, 1.2 Hz, 1 H), 3.79 (dd, J = 12.6, 7.4 Hz, 1 H), 3.70 (dd, J = 12.4, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCIg): δ = 145.00, 131.08, 129.82, 127.22, 125.21 , 124.23, 62.08; IR: 3082, 1635, 1404, 1222, 1039, 933, 850, 711 cm'1; HRMS (ESI) calcd for C7H8OS2 m/z [M+H] +: 173.0095; found: 173.0101 ; [a]J? = +39.1 (c 0.45, CHCI3); HPLC analysts: Chiralcel OD-H (Hex IPA = 90/10, 1.0 mUmin, 254 nm, 22°C), 13.7 (major), 16.6 min, 92% ee.
(R)-2-((2-methytallyl)suifinyl)thiophene(3h) Pale yellow oil; 79% yield; 1H NMR (400 MHz, CDCI3): δ = 7.65 (dd, J = 5.0, 1.1 Hz, 1 H), 7.43 (dd, J = 3.6, 1.1 Hz, 1 H), 7.11 (dd, J = 4.9, 3.7 Hz, 1H), 5.08 - 4.98 (m, 1 H), 4.88 (s, 1 H), 3.82 (d, J = 12.2 Hz, 1H), 3.58 (d, J = 12.3 Hz, 1 H), 1.81 (S, 3H); 13C NMR (100 MHz, CDCI3): 6 = 145.81 , 134.65, 130.98, 129.71 , 127.18, 118.98, 67.65, 22.79; IR: 3080, 2972, 2912, 1649, 1448, 1404, 1377, 1224, 1045, 902, 850, 715 cm"1; HRMS (ESI) calcd for C8H10OS2 m/z [M+H] +: 187.0251 ; found: 187.0257; [aft = +34.3(c 0.72, CHCI3); HPLC analysis: Chiralcel OD-H (Hex IPA = 90/10, 1.0 mL min, 230 nm, 22°C), 1 1.6 (major), 14.2 min, 92% ee. (/¾-2-<but-2-yn-1-ylsuifinyl)thiophene(3i) Pale yellow oil; 77% yield; H NMR (400 MHz, CDCI3): δ = 7.67 (d, J = 5.0 Hz, 1H), 7.52 (d, J = 3.6 Hz, 1 H), 7.17 - 7.10 (m, 1 H), 3.90 - 3.63 (in, 2H), 1.82 (t, J = 2.5 Hz, 3H); 13C NMR (100 MHz, CDCI3): δ = 145.01 , 131.38, 130.04, 127.10, 85.26, 67.59, 49.46, 3.74; IR: 3080, 2902, 2235, 1404, 1224, 1047, 1001, 850, 713 cm- ; HRMS (ESI) calcd for CaH8OS2 m/z [M+HJ +: 185.0095; found: 185.0098; [ctYj = -103.3 (c 0.58, CHCI3); HPLC analysis: Chiralcel AD-H (Hex/lPA = 90/10, 1.0 mL/min, 254 nm, 22°C), 11.6, 14.1 (major) min, 82% ee. (/?)-2-{methylsulfinyl)thiophene{3j) Colourless oil; 65% yield; H NMR (400 MHz, CDCI3): δ - 7.65 (dd, J = 5.0, 1.1 Hz, 1 H), 7.49 (dd, J = 3.6, 1.1 Hz, 1 H), 7.12 (dd, J = 4.9, 3.7 Hz, 1 H), 2.93 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 130.74, 129.19, 127.42, 44.55; IR: 1406, 1033, 954, 717 cm"1; HRMS (ESI) calcd for C5H6OS2 m/z [M+H] +: 146.9938; found: 146.9944; [α]? = +38.7 (c 0.15, CHCI3); HPLC analysis: Chiralcel OD-H (Hex lPA = 95/5, □ 1.0 mL min, 254 nm, 22°C), 34.1 (major), 38.2 min, 77% ee.
(R)-2-(propylsulfinyl)thiophene{3k) pale yellow oil; 66% yield; 1H NMR (400 MHz, CDCI3): δ = 7.65 (dd, J = 5.0, 1.2 Hz, 1 H), 7.47 (dd, J = 3.7, 1.2 Hz, 1 H), 7.12 (dd, J - 5.0, 3.7 Hz, 1 H), 3.12 (dt, J - 12.8, 7.3 Hz, 1 H), 2.91 (dt, J = 12.8, 7.7 Hz, 1 H), 1.84 - 1.67 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H); 3C NMR (100 MHz, CDC!3): δ = 130.88, 129.67, 127.32, 60.22, 16.50, 13.18; IR: 1458, 1404, 1226, 1026, 848, 717 cm"1; HRMS (ESI) calcd for C7H10OS2 m/z [M+H] +: 175.0251 ; found: 175.0257; = +60.5 (c 0.18, CHCI3); HPLC analysis: Chiralcel OD-H (Hex lPA = 95/5, 1.0 mL/min, 230 nm, 22°C), 19.8 (major), 23.0 min, 81 % ee. (R)-2-(octylsulfinyl)thiophene(3l) pale yellow oil; 69% yield; 1H NMR (400 MHz, CDCI3): δ = 7.65 (dd, J = 5.0, 1.2 Hz, 1 H), 7.47 (dd, J = 3.6, 1.2 Hz, 1H), 7.12 (dd, J = 5.0, 3.7 Hz, 1 H), 3.11 (ddd, J = 12.9, 8.5, 6.4 Hz, 1 H), 2.94 (ddd, J = 12.8, 8.6, 7.1 Hz, 1 H), 1.81 - 1.58 (m, 2H), 1.43 (dd, J = 12.7, 5.9 Hz, 2H), 1.36 - 1.15 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H); 3C NMR (100 MHz, CDCI3): δ = 130.87, 129.69, 127.31 , 58.35, 31.68, 29.09, 28.95, 28.58, 22.74, 22.57, 14.04; IR: 2924, 2854, 1458, 1404, 1226, 1049, 848, 717 cm"1; HRMS (ESI) calcd for C12H20OS2 m/z [M+H] +: 245.1034; found: 245.1020; [α] = +34.7 (c 0.32, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/lPA = 95/5, 1.0 mL/min, 230 nm, 22°C), 13.2 (major), 15.9 min, 81 % ee. Example 3
One-mmol scale experiment for synthesis of sulfoxide 6q
Figure imgf000040_0001
1 mmol 18h 245 mg
85% yield 91% ee
A 50 mL RBF was charged with a solution of methyl 3-((3-methylbenzo[b]thiophen-2- yl)sulfinyl)propanoate 4e (282 mg, 1 mmol, 1.0 equiv.), benzyl bromide (143 DL, 1.2 mmol, 1.2 equiv.) and pentanidium 1 d (4.4 mg, 0.0025 mmol, 0.25 mol %) in Et20 (20 mL). The reaction mixture was vigorously stirred at -60 °C for 30 min and then saturated CsOH (1.2 mL, 20 mmol, 20.0 equiv.) was added by syringe in one portion. The reaction mixture was stirred at -60 °C and monitored by TLC. After 4e was completely consumed within 18 h, the reaction was quenched by at 0 °C by addition of 1 M aqueous HC! solution (30 mL) and extracted with Et20 (50 mL * 3). The combined organic layer was washed by brine and dried by a2S04, filtered and concentrated. The sulfoxide 6q was obtained by flash chromatography (silica gel, hexane-ethyl acetate 10:1-2:1 ), as a white solid (245 mg, 85% yield) with 91% ee. Characterisation data provided in Example 4.
Example 4
The general procedure outlined in Example 2 was repeated using different starting materials The results of which are outlined in Table 5.
o 1d (1 mol%) O R2CH2Br(1.2equiv.)
-St -R2 R1' . C f ¾Me saturated aq. CsOH ' R1'
4a-e.5a-f 6a.v 7a-f
CPME/Et20 (1:3)
R1 = aryl, eteroaryl
R2 = aryl
Figure imgf000041_0001
Table 5[al [a] Ratio of dhrneso ~ 4.75:1 , determined by 1H NMR analysis, [b] The reactions were conducted at -40 °C. [c] Data was obtained in the presence of pentanidium 1 c. The absolute configuration was assigned as R by analogy to 6q (see characterisation data below). Characterisation data for the resulting sulfoxides are presented below.
{R)-2-{benzylsuffinyl)-3-methylthiophene(6a> White solid; 85% yield; mp:63.1-63.9 °C; 1H NMR (400 MHz, CDCI3): δ = 7.53 (d, J = 5.0 Hz, 1 H), 7.31 - 7.20 (m, 3H), 7.02 (dd, J = 7.9, 1.4 Hz, 2H), 6.75 (d, J = 5.0 Hz, 1 H), 4.47 (d, J - 12.1 Hz, 1 H), 4.11 (d, J = 12.1 Hz, 1H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 142.22, 138.50, 130.36, 130.19, 129.83, 129.14, 128.62, 128.38, 64.64, 13.83; IR: 2983, 1465, 1419, 1045, 750 cm"1; HRMS (ESI) calcd for C12H12OSz m/z [M+H] +: 237.0408; found: 237.0408; [a]? = -129.5 (c 1.3, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/!PA = 90/10, 1.0 mUmin, 230 nm, 22°C), 20.6 (major), 30.4 min, 91% ee.
(f?)-3-methyl-2-((4-methyibenzyI)sulfinyl)t iophene(6b) Colourless oil; 86% yield; 1H NMR (400 MHz, CDCI3): δ = 7.53 (d, J = 5.0 Hz, H), 7.05 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 5.0 Hz, 1H), 4.44 (d, J = 12.1 Hz, 1 H), 4.08 (d, J - 12.1 Hz, 1H), 2.31 (s, 3H), 1.82 (s, 3H); 3C NMR (100 MHz, CDCI3): δ = 142.23, 138.61 , 138.29, 130.30, 130.08, 129.84, 129.30, 126.01 , 64.32, 21.15, 13.90; IR: 2920, 1614, 1514, 1444, 1381 , 1101, 1045, 821 , 732 cm"1; HRMS (ESI) calcd for C13H14OS2 m/z [M+H] +: 251.0564; found: 251.0562; [o¾f = -162.9 (c 1.13, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 17.5 (major), 24.6 min, 95% ee. (R)-2-((4-chlorobenzyt)sulfinyl)-3-rtiethylthiophene(6c) Colourless oil; 87% yield; 1H NMR (400 MHz, CDCI3): δ = 7.54 (d, J = 5.0 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 5.0 Hz, 1 H), 4.39 (d, J = 12.3 Hz, 1 H), 4.09 (d, J = 12.3 Hz, 1 H), 1.91 (s, 3H); 3C NMR (100 MHz, CDCI3): δ = 142.09, 138.27, 134.58, 131.47, 130.59, 129.98, 128.80, 127.71 , 63.52, 14.02; iR: 1490, 1408, 1095, 1047, 1016 cm'1; HRMS (ESI) calcd for C12HnClOS2 m/z [M+H] +: 271.0018; found: 271.0017; [α]# = -128.4 (c 1.35, CHCi3); HPLC analysis: Chiralcel OJ (Hex/IPA = 95/5, 1.0 mL/min, 230 nm, 22°C), 31.8 (major), 43.1 min, 92% ee.
(R)-3-methyl-2-((4-(trifluoromethyl)benzyl)sulfinyl)thiophene(6d) White solid; 89% yield; mp.107.1-108.5 °C; 1H NMR (400 MHz, CDCI3): δ = 7.54 (dd, J = 8.5, 6.5 Hz, 3H), 7.18 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 5.0 Hz, 1 H), 4.44 (d, J - 12.1 Hz, 1 H), 4.18 (d, J = 12.1 Hz, 1 H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 141.95, 138.31 , 133.37, 130.64(q, J = 10.3 Hz), 130.58, 130.06, 125.50(q, J = 3.7 Hz), 125.22, 122.51 , 63.79, 14.00; 19F NMR (376 MHz, CDCI3): δ = -62.71 ; IR: 2368, 1618, 1419, 1325, 1168, 1126, 1066, 1049, 1018 cm-1; HRMS (ES!) calcd for C13HiiF3OS2 m/z [M+H] +: 305.0282; found: 305.0281; [a]$ = -78.0 (c 1.01, CHCI3); HPLC analysis: Chiralcel OJ (Hex/IPA = 95/5, 1.0 mL/min, 230 nm, 22°C), 21.8 (major), 29.6 miri, 91% ee.
(R)-2-({3-methoxyb©nzyl)sulfinyl)-3-methylthiophene(6e) Colourless oil; 88% yield; 1H NMR (400 MHz, CDCI3): 6 = 7.54 (d, J = 5.0 Hz, 1 H), 7.16 (t, J = 7.9 Hz, 1H), 6.82 (dd, J = 8.3, 2.4 Hz, 1 H), 6.76 (d, J = 5.0 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1 H), 6.51 (s, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 4.06 (d, J - 12.0 Hz, 1 H), 3.70 (s, 3H), 1.84 (s, 3H); ,3C NMR (100 MHz, CDCI3): δ = 159.65, 142.18, 138.85, 130.57, 130.28, 129.86, 129.59, 122.49, 115.14, 114.38, 64.78, 55.18, 13.90; IR: 1600, 1490, 1165, 1045 crrT1; HRMS (ESI) caicd for Cl3H1402S2 m/z [M+H] +: 267.0513; found: 267.0512; [a]£ = -136.7 (c 1.38, CHCI3); HPLC analysis: Chiralcel OJ (Hex IPA = 95/5, 1.0 mL min, 230 nm, 22*C), 53.1 (major), 61.8 min, 94% ee.
{ ?)-3-methyI-2-((naphthalen-2-ylmethyl)sulfinyl)thiophene(6f) Colourless oil; 87% yield; 1H NMR (400 MHz, CDCI3): δ = 7.87 - 7.76 (m, 1 H), 7.72 (t, J = 5.6 Hz, 2H), 7.54 (d, J = 5.0 Hz, 1H), 7.52 - 7.41 (m, 3H), 7.14 (dd, J = 8.4, 1.7 Hz, 1H), 6.72 (d, J = 5.0 Hz, 1 H), 4.63 (d, J = 12.1 Hz, 1 H), 4.28 (d, J = 12.1 Hz, 1 H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 142.17, 138.65, 133.14, 132.89, 130.40, 129.90, 129.68, 128.31 , 127.79, 127.64, 127.40, 126.62, 126.45, 126.42, 64.86, 13.94; IR: 1417, 1045, 1028 cm'1; HRMS (ESI) calcd for Ci6H14OS2 m/z [M+H] +: 287.0564; found: 287.0562; [α]? = -170.6 (c 1.22, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mL/min, 254 nm, 22°C), 26.5 (major), 40.6 min, 92% ee.
1,3-bis(((RH3-methylthiophen-2-yl)sulfinyl)inethyl)benzene(6g) Colourless oil; 87% yield; enantiomers: mesomer = 4.75:1 ; 1H NMR (400 MHz, CDCi3): δ - 7.54 (d, J = 5.0 Hz, 2H), 7.18 (t, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.7, 1.6 Hz, 2H), 6.80 (d, J = 5.0 Hz, 2H), 6.75 (s, 1H), 4.32 (d, J = 12.3, 2H), 4.04 (d, J = 12.3 Hz, 2H), 1.94 (s, 6H);13C NMR (100 MHz, CDCI3): δ = 141.91 , 138.83, 131.99, 130.47, 130.22, 130.08, 130.03, 128.94, 64.01 , 14.08; IR: 2991 , 1606, 1531 , 1487, 1446, 1384, 1217, 1099, 1041 , 1026 cm"1; HRMS (ESI) calcd for C18H1802S4 m/z [M+H] +: 395.0268; found: 395.0258; [α]% = -136.25 (c 1.84, CHCI3); HPLC analysis: Chiralcel OJ (Hex/IPA = 80/20, 1.0 mL min, 230 nm, 22°C), 64.1 (major), 90.7 min, 99% ee. (/?}-2-(benzyl$ulfinyl)-5-methylthiophene(6h) White solid; 85% yield; mp: 109.3-110.8 °C; 1H NMR (400 MHz, CDCI3): δ = 7.33 - 7.27 (m, 3H), 7.12 (dd, J = 6.3, 2.7 Hz, 2H), 6.97 (d, J = 3.6 Hz, 1 H), 6.67 (d, J = 3.6 Hz, 1 H), 4.37 {d, J = 12.4 Hz, 1 H), 4.15 (d, J = 12.4 Hz, 1 H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 146.99, 141.23, 130.88, 130.17, 129.50, 128.65, 128.36, 125.40, 64.61 , 15.86; IR: 1494, 1440, 1213, 1072, 1041 cm"1; HRMS (ESI) calcd for Ci2H12OS2 m/z [M+H] +: 237.0408; found: 237.0439; [α]£ = -132.4 (c 1.0, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 16.5 (major), 24.5 min, 91 % ee. ( ?)-2-((4-chlorobenzyl)suifinyl)-5-methylthiophene{6i) White solid; 86% yield; mp:1 18.2- 119.6 °C; H NMR (400 MHz, CDCI3): δ = 7.30 - 7.21 (m, 2H), 7.06 (s, 1 H), 6.99 (d, J = 3.6 Hz, 1 H), 6.69 (d, J = 3.6 Hz, 1 H), 4.28 (d, J = 12.5 Hz, 1 H), 4.12 (d, J = 12.6 Hz, 1 H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 147.20, 140.89, 134.54, 131.48, 130.94, 128.84, 127.97, 125.51 , 63.66, 15.87; IR: 1492, 1442, 1093, 1045, 1016 cm"1 ; HRMS (ESI) calcd for C12H11CIOS2 m/z [M+H] +: 271 .0018; found: 271.0013; = -93.8 (c 1.19, CHCI3); HPLC analysis: Chiralcel OD-H (Hex IPA = 90/10, 1.0 mL min, 230 nm, 22°C), 1 .5 (major), 23.7 min, 84% ee.
(R)-2-(benzylsulfinyl)-3,5-dimethylthiophene(6j) Colourless oil; 93% yield; *H NMR (400 MHz, CDCI3): δ = 7.34 - 7.16 (m, 3H), 7.06 (dd, J = 7.5, 1.8 Hz, 2H), 6.41 (s, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.08 (d, J = 12.0 Hz, 1 H), 2.49 (s, 3H), 1.73 (s, 3H); 3C NMR (100 MHz, CDCI3): δ = 145.63, 142.91 , 135.43, 130.16, 129.56, 128.58, 128.34, 128.24, 64.50, 15.91 , 13.87; IR: 1556, 1494, 1454, 1242, 1215, 1055, 1033, 831 cm"1; HRMS (ESI) calcd for C13Hl4OS2 m/z [M+H] +: 251.0564; found: 251.0563; = -297.8 (c 1 .16, CHCI3); HPLC G analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 15.6 (major), 25.3 min, 95% ee.
(R)-2-(benzylsulfinyl)benzo[b}thiophene(6k) White solid; 89% yield; mp:166.0-167.1 °C; 1H NMR (400 MHz, CDCI3): δ = 7.96 - 7.84 (m, 1 H), 7.74 (dd, J = 6.8, 2.0 Hz, 1 H), 7.48 - 7.37 (m, 2H), 7.34 (s, 1 H), 7.33 - 7.22 (m, 3H), 7.12 (dd, J = 7.8, 1.3 Hz, 2H), 4.40 (d, J = 12.5 Hz, 1 H), 4.24 (d, J = 12.5 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 145.64, 141.26, 138.09, 130.23, 129.05, 128.71 , 128.55, 126.75, 126.21 , 125.10, 124.80, 122.84, 64.44; IR: 1651 , 1454, 1417, 1027, 1037 cnrf1; HRMS (ESI) calcd for C15H12OS2 m/z [M+H] +: 273.0408; found: 273.0405; [a]$ = -58.9 (c 1 .27, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 32.4 (major), 41.6 min, 92% ee. (R)-2-{{4-methylben2yl)sulfinyI)benzoIb]thiophene{6l) White solid; 91% yield; mp:152.0- 152.5 °C; 1H NMR (400 MHz, CDCI3): δ = 7.94 - 7.84 (m, 1H), 7.75 (dd, J = 6.7, 2.2 Hz, 1 H),
7.47 - 7.38 (m, 2H), 7.37 (s, 1 H), 7.07 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 4.37 (d, J = 12.5 Hz, 1 H), 4.21 (d, J = 12.5 Hz, 1 H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCI3): 6 = 145.85, 141.28, 138.46, 138.12, 130.12, 129.42, 126.76, 126.16, 125.91, 125.07, 124.79, 122.85, 64.21 , 21.19; IR: 1506, 1417, 1049, 819 cm"1; HRMS (ESI) calcd for 016Η14052 m/z [M+H] +: 287.0564; found: 287.0565; [a]£ = -84.5 (c 1.34, CHCI3); HPLC analysis: Chiralcel AD-H (Hex IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 20.3 (major), 27.3 min, 92% ee. (f?)-2-((4-chlorobenzyl)sulftnyI)benzo[b]thiophene(6m) White solid; 81% yield; mp:178.3- 179.0 °C; 1H NMR (400 MHz, CDCI3): δ = 7.95 - 7.82 (m, 1 H), 7.77 (dd, J = 6.5, 2.4 Hz, 1 H),
7.48 - 7.40 (m, 2H), 7.39 (s, 1H), 7.30 - 7.17 (m, 2H), 7.05 (d, J - 8.4 Hz, 2H), 4.31 (d, J = 12.7 Hz, 1 H), 4.23 (d, J = 12.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ = 145.18, 141.26, 138.01 , 134.75, 131.53, 128.89, 127.45, 126.90, 126.36, 125.23, 124.89, 122.86, 63.39; IR: 1247, 1037 cm-1; HRMS (ESI) calcd for C15HnCIOS2 m/z [M+H] +: 307.0018; found: 307.0015; [ ]% = -20.3 (c 1.41 , CHCI3); HPLC analysis: Chiralcel AD-H (Hex IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 25.8 (major), 30.2 min, 90% ee.
( ?)-2-((4-(trifluoromethyl)benzyl)sulflnyl)benzo[b]thiophene(6n) White solid; 80% yield; mp:205.9-207.2 °C; 1H NMR (400 MHz, CDCI3): δ = 7.90 (d, J = 7.6 Hz, 1 H), 7.80 - 7.71 (m, 1 H), 7.53 (d, J = 8.0 Hz, 2H), 7.44 (ddd, J = 7.1 , 6.2, 3.5 Hz, 2H), 7.40 (s, 1H), 7.26 (d, J = 7.8 Hz, 2H), 4.38 (d, J = 12.6 Hz, 1 H), 4.31 (d, J = 12.6 Hz, 1 H); 3C NMR (100 MHz, CDCI3): 5 = 144.96(two peaks), 141.28, 137.98, 133.06, 130.61 , 126.96, 126.47, 125.59 (q, J = 3.8 Hz), 125.32, 124.92(two peaks), 122.87, 63.57; 19F NMR (376 MHz, CDCI3): δ = - 62.73; iR: 2358, 1421 , 1336, 1 1 16, 1070, 1033, 1018 cm"1; HRMS (ESI) calcd for Ci2HnCIOS2 m/z [M+1] +: 271.0018; found: 271.0013. HRMS (ESI) calcd for CieHnF3OS2 m/z [M+H] +: 341.0282; found: 341.0280; [a]Jf = +27.4 (c 0.81 , CHCI3); HPLC analysis: Chiralcel AD-H (Hex/IPA = 90/10, 1.0 mL min, 254 nm, 22°C), 19.9 (major), 24.8 min, 85% ee. (R)-2-((3-methoxybenzyl)sulfinyl)benzo[b]thiophene(6o) White solid; 81 % yield; mp:101.1-102.6 °C; 1H NMR (400 MHz, CDCI3): δ = 7.89 (d, J = 7.2 Hz, 1 H), 7.80 - 7.68 (m, 1 H), 7.47 - 7.37 (m, 2H), 7.36 (s, 1 H), 7.18 (t, J = 7.9 Hz, 1 H), 6.83 (dd, J = 8.3, 2.4 Hz, 1 H), 6.72 (d, J = 7.5 Hz, 1 H), 6.61 (s, 1H), 4.39 (d, J = 12.4 Hz, 1 H), 4.19 (d, J = 12.4 Hz, 1 H), 3.61 (s, 3H); 3C NMR (100 MHz, CDCI3): δ = 159.69, 145.75, 141.23, 138.08, 130.46, 129.71 , 126.80, 126.23, 125.13, 124.80, 122.82, 122.50, 115.09, 114.66, 64.62, 55.06; IR: 1568, 1489, 1321 , 1166, 1155, 1039, 975 cm"1; HRMS (ESI) calcd for C16H1402S2 m/z [M+H] +: 303.0513; found: 303.0515; [a]£ = -71.8 (c 1.42, CHCI3); HPLC analysis: Chiralce! OD-H (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 24.4 (major), 35.1 min, 92% ee.
(R)-2-{{naphthalen-2-ylmethyl)sulfinyi)benzo[b]thiophene(6p) White solid; 90% yield; mp:198.3-199.7 °C; 1H NMR (400 MHz, CDCi3): 6 = 7.90 (d, J = 8.0 Hz, 1 H), 7.84 - 7.77 (m, 1 H), 7.71 (dd, J = 18.3, 8.0 Hz, 3H), 7.62 (d, J = 6.2 Hz, 1 H), 7.52 - 7.36 (m, 4H), 7.34 (s, 1 H), 7.21 (dd, J = 8.4, 1.7 Hz, 1 H), 4.57 (d, J = 12.5 Hz, 1 H), 4.41 (d, J = 12.5 Hz, 1 H); 13C NMR (100 MHz, CDCI3): 6 = 145.72, 141.28, 138.09, 133.17, 133.06, 129.83, 128.48, 127.89, 127.68, 127.43, 126.87, 126.53, 126.51, 126.43, 126.24, 125.11 , 124.84, 122.85, 64.80; IR: 1421 , 1047 cm-1; HRMS (ESI) calcd for Ct9H14OS2 m/z [M+H] +: 323.0564; found: 323.0569; [a]# = -95.3 (c 0.78, CHCI3); HPLC analysis: Chiralcel AD-H (Hex/IPA = 90/10, 1.0 mL min, 230 nm, 22°C), 32.8 (major), 42.6 min, 91% ee.
(R)-2-{benzylsulfiny])-3-methylbenzo[b]thiophene(6q) White solid; 83% yield; mp: 137.8- 138.7 °C; 1H NMR (400 MHz, CDCI3): δ = 7.90 (dd, J = 7.0, 1.1 Hz, 1 H), 7.60 (dd, J = 7.1 ,
1.5 Hz, 1 H), 7.50 - 7.37 (m, 2H), 7.27 (dt, J = 5.1 , 3.8 Hz, 1 H), 7.20 (dd, J = 10.1 , 4.7 Hz,
2H), 7.07 - 6.97 (m, 2H), 4.54 (d, J = 12.0 Hz, 1 H), 4.22 (d, J = 12.0 Hz, 1H), 1.90 (s, 3H);
13C NMR (100 MHz, CDCI3): 5 = 140.47, 139.88, 139.05, 136.99, 130.20, 129.03, 128.67,
128.47, 126.42, 124.69, 123.12, 122.74, 64.12, 12.04; IR: 1454, 1107, 1045, 960 cm"1; HRMS (ES!) calcd for C16H14OS2 m/z [M+H] +: 287.0564; found: 287.0567; = -227.2 (c
1.3, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/iPA = 90/10, 1.0 mL/min, 254 nm, 22°C),
31.4 (major), 64.6 min, 95% ee.
Crystal data for (R)-6q: [C16H14OS2], M = 286.39, monoclinic, P 1 21 1 , a = 11.0865(5), b = 5.5227(3), c = 11.5834(5) A, a = 90, β = 101.001 (2), γ = 90°, V = 696.19(6) A3, Z = 2, pealed = 1.366 g/cm3, p(CuKa) = 0.370 mm-1 , T = 103(2) , Wavelength - 0.71073 A, colourless blocks, Bruker X8 APEX X-ray diffractionmeter; 2431 independent measured reflections, F2 refinement, R1 (obs) = 0.0428, wR2(all) = 0.1296, 2188 independent observed absorption- corrected reflections, 173 parameters. CCDC 1006625 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request cif.
( ?)-3-methyl-2-((4-methylbenzyl)sulfinyl)benzo[b]thiophene(6r) White solid; 80% yield; mp:158.5-159.7 °C; 1H NMR (400 MHz, CDCI3): 6 = 7.94 - 7.87 (m, 1 H), 7.62 (dd, J = 6.9, 1.7 Hz, 1 H), 7.43 (pd, J = 7.1 , 1.3 Hz, 2H), 7.06 - 6.97 (m, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.50 (d, J = 12.1 Hz, 1 H), 4.19 (d, J = 12.1 Hz, 1 H), 2.30 (s, 3H), 1.94 (s, 3H); 3C NMR (100 MHz, CDCI3): δ = 140.49, 140.06, 139.09, 138.38, 136.94, 130.08, 129.34, 126.37, 125.88, 124.65, 123.12, 122.75, 63.80, 21.15, 12.13; IR: 1427, 1255, 1105, 1039, 1010, 966 cm"1; HRMS (ESI) calcd for Cl7H16OS2 m/z [M+H] +: 301.0721 ; found: 301.0716; [a]$ = -240.2 (c 1.42, CHCI3); HPLC analysis: Chiralcel OJ (Hex IPA - 95/5, 1.0 mL min, 254 nm, 22°C), 46.2, 64.5(major) min, 94% ee.
{ ?)-2-({4-chforoben2yl)sulfinyl)-3-methylbenzo[b]thiophene(6s) White solid; 83% yield; mp:185.2-186.8 °C; 1H NMR (400 MHz, CDCI3): δ = 7.93 - 7.83 (m, 1 H), 7.69 - 7.60 (m, 1 H), 7.45 (dq, J = 7.3, 5.9 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 4.46 (d, J = 12.2 Hz, 1 H), 4.20 (d, J = 12.2 Hz, 1 H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 140.47, 139.64, 139.01, 136.98, 134.67, 131.49, 128.87, 127.61 , 126.60, 124.84, 123.14, 122.86, 63.11 , 12.29; IR: 2985, 1421 , 1095, 1045 cm'1; HRMS (ESI) calcd for d6H13CIOS2 m/z [M+H] +: 321.0175; found: 321.0177; - -203.7 (c 1.73, CHCI3); HPLC analysis: Chiralcel OJ (ΗΘΧ/ΙΡΑ = 90/10, 1.0 mL/min, 254 nm, 22°C), 35.7, 39.9(major) min, 91% ee. (A¾)-3-methyI-2-{(4-{trifluoron(iethyl)benzyl)sulfinyI)benzo[b]thiophene(6t) White solid; 75% yield; mp:178.7-180.0 °C; 1H NMR (400 MHz, CDCI3): δ = 7.90 (dd, J = 6.9, 1.5 Hz, 1 H), 7.65 (dd, J = 6.9, 1.8 Hz, 1H), 7.54 - 7.37 (m, 4H), 7.20 (d, J - 8.0 Hz, 2H), 4.53 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 1 H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 140.46(two peaks), 139.52, 138.97, 136.91 , 133.27, 130.57, 126.70, 125.57 (q, J = 3.7 Hz), 124.92, 123.13, 122.87(two peaks), 63.31, 12.24; 19F NMR (376 MHz, CDCI3): δ = -62.72; IR: 1620, 1421 , 1325, 166, 122, 1066, 1039, 1018 cm-1; HRMS (ESi) calcd for C17H13F30S2 m/z [M+H] +: 355.0438; found: 355.0446; [a]$ - -122.1 (c 1.5, CHCI3); HPLC analysis: Chiralcel OJ (Hex IPA = 95/5, 1.0 mL/min, 254 nm, 22°C), 41.0, 49.4(major) min, 89% ee. {R)-2-((3-methoxybenzyl)sulfinyl)-3-methylbenzoEb]thiophene(6u) Pale yellow oil; 90% yield; 1H NMR (400 MHz, CDCI3): δ = 7.90 (dd, J = 6.9, 1.6 Hz, 1 H), 7.69 - 7.58 (m, 1 H), 7.43 (pd, J - 7.1 , 1.4 Hz, 2H), 7.17 - 7.04 (m, 1 H), 6.80 (dd, J = 8.3, 1.9 Hz, 1 H), 6.66 (d, J = 7.5 Hz, 1 H), 6.50 - 6.35 (m, 1 H), 4.52 (d, J = 11.9 Hz, 1 H), 4.17 (d. J = 11.9 Hz, 1 H), 3.47 (s, 3H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 159.66, 140.42, 139.99, 139.05, 137.13, 130.42, 129.63, 126.46, 124.76, 123.09, 122.77, 122.50, 114.82, 114.76, 64.26, 54.92, 12.12; !R: 1600, 1490, 1438, 1165, 1105, 1045 crn 1; HRMS (ESI) calcd for C17H1B02S2 m/z [M+H] +: 317.0670; found: 317.0674; [α}$ = -184.8 (c 1.66, CHCI3); HPLC analysis: Chiralcel OJ (Hex/IPA = 90/10, 1.0 mL/min, 210 nm, 22°C), 37.5, 45.2(major) min, 95% ee.
(R)-3-methyl-2-({naphthalen-2-ylmethyl)sulfinyl)benzo[b]thiophene(6v) White solid; 88% yield; mp:168.5-169.8 °C; 1H NMR (400 MHz, CDCI3): δ = 7.91 (d, J = 7.9 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 7.7 Hz, 1 H), 7.53 (d, J = 7.3 Hz, 2H), 7.50 - 7.35 (m, 4H), 7.12 (dd, J = 8.4, 1.7 Hz, 1 H), 4.69 (d, J = 12.1 Hz, 1 H), 4.38 {d, J = 12.1 Hz, 1 H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 140.45, 140.09, 139.10, 136.93, 133.11 , 132.90, 129.70, 128.37, 127.75, 127.63, 127.36, 126.50, 126.49, 126.44, 124.70, 123.10, 122.75(two peaks), 64.40, 12.19; IR: 1102, 1037, 960, 746 cm"1; HRMS (ESI) calcd for C20Hi6OS2 m/z [M+H] +: 337.0721; found: 337.0724; [a]g = -249.3 (c 1.44, CHCI3); HPLC analysis: Chiralcel OD-H (Hex IPA = 70/30, 1.0 mL min, 254 nm, 22°C), 19.0 (major), 46.3 min, 92% ee.
(/^-5-methoxy-1-methyl-2-((4-methylbenzyl)sulfinyl)-1 H-benzoId]imidaz:ole(7a)
Colourless oil;99% yield; 1H NMR (400 MHz, CDCI3): δ = 7.27 (d, J = 6.6 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1H), 7.03 (t, J = 8.7 Hz, 3H), 6.94 (d, J = 7.5 Hz, 2H), 4.62 (d, J = 12.8 Hz, 1 H), 4.44 (d, J = 12.8 Hz, 1 H), 3.88 (s, 3H), 3.48 (s, 3H), 2.31 (s, 3H); 3C NMR (100 MHz, CDCI3): δ = 157.00, 150.11 , 142.97, 138.66, 131.32, 130.43, 129.36, 125.81 , 115.35, 1 0.11, 102.07, 60.52, 55.77, 30.01 , 21.15; IR: 1490, 1411 , 1346, 1199, 1047, 1029 cm"1; HRMS (ESI) calcd for Ci7H1 sN202S m/z [M+H] +: 315.1167; found: 315.1171 ; [α]$ = +134.96 (c 1.35, CHCI3); HPLC analysis: Chiralcel OJ (Hex/IPA = 70/30, 1.0 mL/min, 230 nm, 22eC), 25.3(major), 42.1 min, 90% ee.
( ?)-1-((4-chlorobenzyl)sulfinyl)-3,5-dimethylbenzene{7b) White solid; 88% yield; mp:98.7-100.4 °C; 1H NMR (400 MHz, CDCI3): δ - 7.30 - 7.18 (m, 2H), 7.10 (s, 1 H), 6.99 (s, 2H), 6.94 (d, J = 8.4 Hz, 2H), 3.98 (s, 2H), 2.33 (s, 6H); 13C NMR (100 MHz, CDCI3): 6 = 142.20, 138.92, 134.32, 132.95, 131.65, 128.46, 127.87, 121.75, 62.59, 21.16; IR: 3049, 2920, 1606, 1492, 1408, 1097, 1051 cm"1; HRMS (ESI) calcd for Cl5H15CIOS m/z [M+H] +: 279.0610; found: 279.0612; [a] J? - +132.92 (c 1.47, CHCI3); HPLC analysis: Chiralcel AD-H (Hex/IPA = 90/ 0, 1.0 mL/min, 230 nm, 22°C), 10.6, 12.2(major) min, 88% ee.
(R)-2-((4-chlorobenzyl)sulfinyI)furan(7c) Colourless oil; 95% yield; 1H NMR (400 MHz, CDCI3): δ = 7.69 (dd, J = 1.7, 0.7 Hz, 1H), 7.30 - 7.19 (m, 3H), 7.10 - 6.96 (m, 2H), 6.75 (dd, J = 3.4, 0.6 Hz, 1 H), 6.46 (dd, J = 3.4, 1.8 Hz, 1 H), 4.41 (d, J = 12.6 Hz, 1H), 4.34 (d, J = 12.6 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ - 150.33, 146.83, 134.55, 131.31 , 128.91 , 127.72, 117.24, 11 1.45, 58.58; IR: 3051 , 1490, 1460, 1095, 1047, 1008 cm"1; HRMS (ESI) calcd for CnHBCI02S m/z [M+H] +: 241.0090; found: 241.0082; [a]$ = -77.5 (c 1.14, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mL min, 230 nm, 22°C), 20.6(major), 27.4min, 81 % ee. (/?)-3-(benzylsulfinyl)-2-methylfuran(7d) Colourless oil; 73% yield; 1H NMR (400 MHz, CDCI3): δ = 7.37 (d, J = 2.1 Hz, 1 H), 7.31 - 7.20 (m, 3H), 7.06 (dd, J = 7.3, 2.1 Hz, 2H), 6.66 (d, J = 2.0 Hz, 1 H), 4.32 (d, J = 12.1 Hz, 1 H), 4.03 (d, J = 12.1 Hz, 1 H), 1.89 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 154.58, 142.36, 130.19, 129.46, 128.61, 128.26, 120.79, 106.69, 61.67, 1 1.70; IR: 1589, 1514, 1454, 1388, 1228, 1 126, 1043, 1012 cm'1; HRMS (ESI) calcd for Ci2H1202S m/z [M+H] +: 237.0408; found: 237.0401 ; [af = -41.6 (c 0.68, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mUmin, 254 nm, 22°C), 14.8(major), 21.1 min, 81 % ee.
(R)-2-((4-chlorobenzyl)sulfinyl)benzofuran(7e) White solid; 83% yield; mp:156.3-157.4 °C; H NMR (400 MHz, CDCI3): δ = 7.60 (dd, J = 8.1 , 4.6 Hz, 2H), 7.45 (dd, J = 11.5, 4.3 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2H), 7.12 - 7.01 (m, 3H), 4.50 (d, J = 12.8 Hz, 1 H), 4.39 (d, J = 12.8 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ = 156.46, 153.22, 134.72, 131.45, 128.95, 127.41 , 126.98, 126.47, 124.00, 122.38, 112.90, 111.96, 58.71; IR: 1490, 1166, 1097, 1049, 2016 cm"1; HRMS (ESI) calcd for C15HnCI02S m/z [M+H] +: 291.0247; found: 291.0249; = -5.48 (c 0.73, CHCI3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 95/5, 1.0 mUmin, 230 nm, 22°C), 37.8(major), 64.1 min, 79% ee. {R)-2-{(4-c lorobenzyl)suifinyl)pyridine(7f) Colourless oil; 84% yield; H NMR (400 MHz, CDCI3): δ = 8.66 (dd, J = 4.7, 0.7 Hz, 1 H), 7.78 (td, J = 7.7, 1.7 Hz, 1 H), 7.57 (d, J = 7.9 Hz, 1 H), 7.34 (ddd, J = 7.6, 4.7, 1.1 Hz, 1 H), 7.23 - 7.12 (m, 2H), 6.98 - 6.81 (m, 2H), 4.32 (d, J = 13.2 Hz, 1 H), 4.04 (d, J = 13.2 Hz, 1 H); 13C NMR (100 MHz, CDCI3): δ - 163.33,149.33, 137.73, 134.30, 131.48, 128.41 , 127.62, 124.65, 120.70, 58.70; IR: 3051 , 1575, 1490, 1423, 1095, 1051 , 1037, 1016 cm"1; HRMS (ESI) calcd for Ci2H10CINOS m/z [M+H] +: 252.0250; found: 252.0248; [α]# = +224.64 (c 1.27, CHCI3); HPLC analysis: Chiralcel OD-H (Hex IPA = 95/5, 1.0 mL/min, 230 nm, 22°C), 24.0, 28.0(major) min, 71 % ee.
Example 5
Mechanistic Study
1 (1 mol %)
BnX (1.2 equiv.)
X = Br, CI
CPME
-60 "C
Entry Catalyst X Time Product Yield ee [%]tc]
[h]
1 la - 24 8 40 -
2M . Br 1 - - -
3 la CI 48 8 27 -
4 lb CI 48 3a:8 (1:2)M 9 83
5 lc CI 24 3a 15 91
6 Id CI 24 3a 29 90
Table 6Ial
[a] Reactions were performed by using 2a (0.02 mmol) and benzyl halides (0.024 mmol) in the presence of 1 mol % of pentanidiums in CPME (0.4 mL) and saturated aqueous CsOH (24 μ[_). [b] Yield of the isolated product, [c] Determined by HPLC analysis. [dj.The substrate 2a decomposed under basic conditions without phase-transfer catalysts, [e] The ratio was determined by "Ή NMR analysis.
Methyl 3-{(thiophen-2-ylthio)oxy)propanoate[8] Colorless oil; H NMR (400 MHz, CDCI3). δ = 7.75 (dd, J = 5.0, 1.3 Hz, 1H), 7.71 (dd, J - 3.8, 1.3 Hz, 1 H), 7.18 (dd, J = 4.9, 3.8 Hz, 1H), 3.67 (s, 3H), 3.59 - 3.46 (m, 2H), 2.88 - 2.74 (m, 2H); 13C NMR (100 MHz, CDCI3): δ = 170.29, 139.46, 134.57, 134.47, 128.05, 52.91 , 52.36, 28.01 ; IR: 1732, 1438, 1402, 1367, 1317, 1261 , 1155, 1 132, 1020 cm"1; HRMS (ESI) calcd for C8H10O3S2 m/z [M+H] +: 219.0150; found: 219.0141. Example 6
For the sulfoxides 7g-7m, about 50% enantioselectivity can be achieved by using pentanidium 1d (Table 7) using the reaction conditions used herein.
entry R Product Time(h) ee (%)
1 PhCH2 7g 22 52 2 4-MeC6H4CH2 7h 84 54 3 4-OMeC6H4CH2 7i 84 52 4 4-ClC6H4CH2 7j 36 54 5 2-MCC6H4CH2 7k 36 57 6 2-EtC6H4CH2 71 36 64 7 'Bu Tab 7|me 7,aJ 24 53
[a] Reactions were performed by using 2a (0.02 mmol), and 4-ch!orobenzyl bromide (0.024 mmol) in the presence of 1 mol % of pentanidium 1 d and saturated aqueous CsOH solution (24 μΙ_) in CPME (0.4 mL). [b] Determined by HPLC analysis.
Characterisation data for the above-mentioned compounds is provided below.
7g; HRMS (ESI) calcd for C13HnCIOS m/z [M+H] +: 251.0297; found: 251.0286; HPLC analysis: Chiralcel OD-H (Hex IPA = 95/5, 1.0 mL min, 230 nm, 22°C), 13.5(major), 15.7 min, 52% ee.
7h; HRMS (ESI) calcd for C14H13CIOS m/z [M+H] +: 265.0454; found: 265.0452; HPLC analysis: Chiralcel OD-H (Hex IPA = 90/10, 1.0 mL min, 230 nm, 22°C), 14.0(major), 15.5 min, 54% ee.
7i; 1H NMR (400 MHz, CDCI3): δ = 7.34 - 7.27 (m, 2H), 7.24 - 7.15 (m, 2H), 6.97 - 6.91 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.03 - 3.90 (m, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCi3): δ = 162,11 , 134.25, 133.17, 131.63, 128.53, 127.62, 126.23, 114.43, 62.53, 55.47; HRMS (ESI) calcd for Ci4Ht3CI02S m/z [M+H] +: 281.0403; found: 281.0405; HPLC analysis: Chiralcel OJ (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 22.0, 30.2(major) min, 52% ee. 7j; HRMS (ESI) calcd for Ci3H1QCI2OS m/z [M+HJ +: 284.9908; found: 284.9904; HPLC analysis: C iralcel AD-H (Hex/IPA = 90/10, 1.0 mL/min, 230 nm, 22°C), 11 .6, 12.9(major) min, 54% ee.
7k; 1H NMR (400 MHz, CDCI3): δ = 7.60 (dd, J = 7.4, 1.8 Hz, H), 7.42 - 7.26 (m, 2H), 7.24 - 7.17 (m, 2H), 7.14 (d, J = 6.7 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 2H), 4.13 - 3.84 (m, 2H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 140.82, 135.08, 134.39, 131.62, 130.98, 130.29, 128.52, 127.65, 127.08, 124.29, 60.70, 18.03; LRMS (ESI) m/z 265.06 (M + H+); HRMS (ESI) calcd for Ci H13CIOS m/z [M+H] +: 265.0454; found: 265.0463; HPLC analysis: Chiralcel OD-H (Hex/IPA - 90/10, 1.0 mL/min, 230 nm, 22°C), 13.3(major), 15.4 min, 57% ee.
7\ NMR (400 MHz, CDCI3): δ = 7.61 (dd, J = 7.8, 1.0 Hz, 1 H), 7.41 (td, J ~ 7.4, 1.1 Hz, 1 H), 7.33 (t, J = 7.1 Hz, 1 H), 7.24 - 7.15 (m, 3H), 6.90 (d, J ~ 8.3 Hz, 2H), 3.98 (q, J = 12.8 Hz, 2H), 2.61 (dq, J = 15.0, 7.5 Hz, 1 H), 2.43 (dq, J = 14.9, 7.5 Hz, 1 H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCI3): δ = 141 .39, 140.33, 134.39, 131.62, 131.30, 128.54, 128.41 , 127.81 , 127.12, 124.32, 61 .51 , 24.47, 14.99; HRMS (ESI) calcd for C15H15CIOS m/z [M+H] +: 279.0610; found: 279.0613; HPLC analysis: Chiralcel OD-H (Hex/IPA = 90/10, 1.0 mlJmin, 230 nm, 22°C), 10.5(major), 12.7 min, 64% ee.
7m; 1H NMR (400 MHz, CDCI3): δ = 7.32 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 3.77 (d, J = 12.8 Hz, 1 H), 3.57 (d, J = 12.8 Hz, 1 H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCI3): δ = 134.08, 131.32, 130.49, 128.98, 53.82, 51.98, 23.00; HRMS (ESI) calcd for CnH15CIOS m/z [M+H] +: 231.0610; found: 231.0607; HPLC analysis: Chiralcel AD-H (Hex IPA = 95/5, 1.0 mL min, 230 nm, 22°C), 15.4, 23.5(major) min, 53% ee.

Claims

Claims
1. A compound of formula (I);
Figure imgf000053_0001
wherein:
A represents an anionic counterion; and
R represents a fragment of formula (II):
Figure imgf000053_0002
wherein:
the dotted line represents the point of attachment to the rest of molecule of formula
(!); and
each X independently represents Ci, Br or I.
2. The compound of Claim 1 , wherein each X is the same and represents CI, Br or I.
3. The compound of Claim 2, wherein X represents (I).
4. The compound of any one of the preceding claims, wherein the compound of formula (I) is a compound of formula (la) or (lb):
Figure imgf000054_0001
Figure imgf000054_0002
5. The compound of any one of the preceding claims, wherein A is an anionic counterion selected from the group consisting of CI', Br", Γ and F.
6. The compound of any one of the preceding claims selected from:
(a) (4S,5S)-2-({{4S,5S)-1 I3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4,5-diphenylimidazolidin- 2-ylidene)amino)-1 ,3-bis(3,5-di-tert-butyl-2-chlorobenzyl)-4J5-dipheny!-4,5-dihydro-1H- imidazol-3-ium chloride;
(b) (4S,5S)-2-(((4S,5S)-1 ,3-bis{2-bromo-3,5-di-tert-butylbenzyl)-4,5 diphenylimidazolidin-
2- ylidene)amino)-1 ,3-bis(2-bromo-3,5-di-tert-butylbenzyl)-4,5-diphenyl-4,5-dihydro-1 H- imidazol-3-ium chloride; and
(c) (4S,5S)-2-(((4S,5S)-1 ,3-bis(3,5-di-tert-butyl-2-iodobenzyl)-4,5-diphenylimidazolidin-2- ylidene)amino)-1,3-bis(3,5-di-tert-butyl-2-iodobenzyi)-4,5-diphenyi-4,5-dihydro-1H-imidazol-
3- ium chloride.
7. Use of a compound as described in any one of Claims 1 to 6 as a catalyst for a chemical reaction.
8. The use of Claim 7, wherein the chemical reaction is the preparation of sulfoxides.
9. The use of Claim 7 or Claim 8, wherein the chemical reaction results in one or more enantioenriched products.
10. A method of producing an enantoenriched sulfoxide, said method comprising, reacting a compound of formula (III):
o
Figure imgf000055_0001
with a compound of formula (IV):
R3-X1 (IV)
in the presence of a catalytic amount of a compound of formula (I) as defined in any one of Claims 4 to 6, a base and a solvent, to provide the enantioenriched sulfoxide, wherein:
Ri represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted alkyl group;
R2 represents and electron withdrawing group; and
R3 represents a substituted or unsubstituted alkyl group.
11. The method of Claim 10, wherein the solvent comprises an ether.
12. The method of Claim 10, wherein the ether is selected from one or more of cyclopentyl methyl ether and diethyl ether.
13. The method of any one of Claims 10 to 12, wherein the reaction is conducted at a temperature of from -50°C to -80°C.
14. The method of any one of Claims 10 to 13, wherein the base is cesium hydroxide.
15. The method of any one of Claims 10 to 14, wherein R2 represents -C(0)2 e, -C(0)2Et, -C(0)2'Bu, -C(0)2Ph, S02Ph and -CN.
PCT/SG2015/050309 2014-09-09 2015-09-09 Catalysts for making chiral heterocyclic sulfoxides WO2016039691A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SG10201405585U 2014-09-09
SG10201405585U 2014-09-09

Publications (1)

Publication Number Publication Date
WO2016039691A1 true WO2016039691A1 (en) 2016-03-17

Family

ID=55459337

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SG2015/050309 WO2016039691A1 (en) 2014-09-09 2015-09-09 Catalysts for making chiral heterocyclic sulfoxides

Country Status (1)

Country Link
WO (1) WO2016039691A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017164813A1 (en) * 2016-03-22 2017-09-28 Nanyang Technological University Ion pair catalysis of tungstate and molybdate
WO2023063884A3 (en) * 2021-10-12 2023-07-27 Nanyang Technological University Generation of chiral sulfinate esters
KR20230140969A (en) * 2022-03-30 2023-10-10 고려대학교 산학협력단 Method for preparing thiobenzimidazole derivatives, and novel intermediates therefor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012057709A1 (en) * 2010-10-28 2012-05-03 National University Of Singapore Novel phase transfer catalysts
CN102658199A (en) * 2012-05-14 2012-09-12 惠州市莱佛士制药技术有限公司 Novel asymmetric phase-transfer catalyst pentaazabicyclo and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012057709A1 (en) * 2010-10-28 2012-05-03 National University Of Singapore Novel phase transfer catalysts
CN102658199A (en) * 2012-05-14 2012-09-12 惠州市莱佛士制药技术有限公司 Novel asymmetric phase-transfer catalyst pentaazabicyclo and preparation method thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GELAT, F. ET AL.: "Organocatalytic Asymmetric Synthesis of Sulfoxides from Sulfenic Acid Anions Mediated by a Cinchona-Derived Phase-Transfer Reagent.", ORG. LETT., vol. 13, no. 12, 20 May 2011 (2011-05-20), pages 3170 - 3173, [retrieved on 20150921] *
MA, T. ET AL.: "Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions.", J. AM. CHEM. SOC., vol. 133, no. 9, 11 February 2011 (2011-02-11), pages 2828 - 2831, XP055087770, [retrieved on 20150917], DOI: doi:10.1021/ja1098353 *
YANG, Y. ET AL.: "Pentanidium-Catalyzed Enantioselective a-Hydroxylation of Oxindoles Using Molecular Oxygen.", ORG. LETT., vol. 14, no. 18, 4 September 2012 (2012-09-04), pages 4762 - 4765, [retrieved on 20150917] *
ZONG, L. ET AL.: "Catalytic Enantioselective Alkylation of Sulfenate Anions to Chiral Heterocyclic Sulfoxides Using Halogenated Pentanidium Salts.", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 53, no. 44, 10 September 2014 (2014-09-10), pages 11849 - 11853, [retrieved on 20150917] *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017164813A1 (en) * 2016-03-22 2017-09-28 Nanyang Technological University Ion pair catalysis of tungstate and molybdate
US10710061B2 (en) 2016-03-22 2020-07-14 Nanyang Technological University Ion pair catalysis of tungstate and molybdate
WO2023063884A3 (en) * 2021-10-12 2023-07-27 Nanyang Technological University Generation of chiral sulfinate esters
KR20230140969A (en) * 2022-03-30 2023-10-10 고려대학교 산학협력단 Method for preparing thiobenzimidazole derivatives, and novel intermediates therefor
KR102729195B1 (en) * 2022-03-30 2024-11-13 고려대학교 산학협력단 Method for preparing thiobenzimidazole derivatives, and novel intermediates therefor

Similar Documents

Publication Publication Date Title
KR20050032107A (en) Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds
AU2006345861B2 (en) Process for the preparation of optically pure or optically enriched enantiomers of sulphoxide compounds
Barakat et al. Highly enantioselective Friedel–Crafts alkylation of indoles with α, β-unsaturated ketones with simple Cu (II)–oxazoline–imidazoline catalysts
WO2016039691A1 (en) Catalysts for making chiral heterocyclic sulfoxides
CN101565393A (en) 3-(substituted bisulfonyl fluromethane)-1-propylene compound, synthetic method and applications thereof
Fan et al. Diastereo-and enantioselective nitro-Mannich reaction of α-substituted nitroacetates to N-phosphoryl imines catalyzed by cinchona alkaloid thiourea organocatalysts
US10710061B2 (en) Ion pair catalysis of tungstate and molybdate
CA2539176C (en) Process for the preparation of chiral propionic acid derivatives
CN103910758B (en) The preparation method of a kind of axial chirality dibenzyl phosphine oxide and axial chirality dibenzyl phosphine
CN104910098B (en) Synthesis method of 2-arylbenzothiazole compound
CN113666826B (en) Aryl or heteroaryl methoxylation reaction method
Han et al. Chiral ferrocenyl P, S-ligands for highly efficient copper-catalyzed asymmetric [3+ 2] cycloaddition of azomethine ylides
US9512155B2 (en) Chiral phosphines for palladium-catalyzed asymmetric α-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity
CN102690227A (en) Optical active tetrahydropyridine derivative and preparation method thereof
JPWO2005070875A1 (en) Method for producing amines
WO2015029062A1 (en) A process for the preparation of anti-inflammatory aroylbenzofuran compounds
CN101318146A (en) Application of Dehydroabietine Aminothiourea Catalyst in High Enantiomeric Two-handed Synthesis of Chiral Compounds
Xie et al. Benzothiazole-Directed Enantioselective Borylation of Secondary Benzylic C–H Bonds Using Iridium Catalysis
CN115286635B (en) A kind of synthesis method of chiral paracyclic pyrazolinone compounds
KR101286617B1 (en) Method for preparing ［1,2,3］-oxathiazolidine-2,2-dioxide or ［1,2,5］-thiadiazolidine-1,1-dioxide derivatives
CN103209978B (en) Phase-transfer catalyst
CN103333144B (en) 2-sulfenyl-3-chlorinated benzofuran compound as well as synthesis method and application thereof
Wang et al. A new cost-effective Ru-chloramphenicol base derivative catalyst for the asymmetric transfer hydrogenation/dynamic kinetic resolution of N-Boc α-amino-β-ketoesters and its application to the synthesis of the chiral core of vancomycin
KR101345749B1 (en) Method for the stereoselective preparation of 4,5-diaryl 5-membered ring sulfamidates
CN112961183B (en) C3-phosphono substituted benzohydrofuran and benzofuran compounds and preparation method thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15840144

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15840144

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载