Sulfines

Tear-inducingreac1veintermediates

BradGilbert9/29/2015

R2 S

R1 [O]

R2 S

R1

O

OSO

PPh

PhPh S

O

R2

R1

R2

R1+

EnvisionedbyStaudingerasaWiBgadductwithsulfurdioxide

TheS-oxideofthiocarbonylcompounds,assulfoxidesaretothioethers.R1andR2neednotbealkyl/arylinordertobeclassifiedasasulfine,muchlikeallenesandketenes.

H.Staudinger,W.T.K.Braunholtz,J.Chem.Soc.1922,300

ALiRle-SeenFunc1onalGroup

Synthesis:EarlyARempts•  Ini1alaRemptsbyStaudingeronlygavesuspecteddecomposi1on

products

•  Didnotobservepurported“thionylmethylene”intermediate,onlyproposeditsexistence

•  SuggestedextrusionofSOanddimeriza1onofdiphenylcarbene

Ph

Ph

CO

OSO

Et2O

Ph

Ph

SO+ Ph

PhPh

Ph

Ph

Ph

S O

O

O

Staudinger,E.,Pfenninger,F.Ber.Dtsch.Chem.Ges.1916,49,1941.King,J.F.,Durst,T.Can.J.Chem.1966,44,819

FirstSuccessfulSynthesis•  WedekindandSchenkobtainedserendipitouslywhattheydubbed

“chlorosulfoxid-camphor”

•  Structurewasnotconfirmedasthechlorosulfineun1l40yearslater,by

KingandDurst–  Werealsoabletoobtainchlorophenylsulfinewithsimilarcondi1ons

OSO2Cl Et3N or Py

OSO

Cl

O

SCl

O

SO2Cl

Et3N

cyclohexane-60 ºC

SO

Cl

anilineS

HNPh

O

Wedekind,E.,Schenk,D.,Stüsser,R.,Ber.1923,56,633King,J.F.,Durst,T.TetrahedronLe:.1963,585

MechanismforSulfonylChlorideElimina1on

•  Mixedanhydridesupportedbyacceleratedrateandincreasedyieldwithaddi1onof1equivalentofTsCl

RCH + SO2

RR

King,J.F.,Durst,T.TetrahedronLe:.1963,585

R SCl

O O

H

R SO

OR S

O-

O

Cl

RCH2SO2Cl

R SO

OS

O OR

ClH

R S

Cl

O

EarlySyntheses•  Kitamuraobservedtheoxida1onofthioamideswithhydrogenperoxide,

butincorrectlyassignedthestructureastheimino“tautomer”

•  Twodecadeslater,WalterprovedthestructuretobetheS-oxidewithUV,infraredspectroscopyand1tra1onofthioamides,thioamideS-oxidesandsulfenicacids.

NH2

SH2O2MeOH NH2

SO

NH

SOH

Kitamura,R.J.Pharm.Soc.Jpn.1938,58,246Walter,W.JustusLiebigsAnn.Chem.1960,35,633

FirstThioketoneS-oxides•  DiekmannandSheppardisolatedfluorenylidenesulfinein1964

•  Obtainedin75%yieldasorangecrystals.Decomposedslowlyatrt,rapidlyat

mel1ngpoint(111ºC),yieldingdifluorenylideneandSO2

•  Werealsoabletoprepareisopropylidenesulfineat-20ºCindichloromethaneandobservethechemicallynonequivalentmethylsignalsby1HNMR

LiSO2

S OLiO

SOCl2S Cl

O

S ClO

Et3N

Et2O, rtinstantaneous

SO

Sheppard,W.A.,Diekmann,J.J.Am.Chem.Soc.1964,86,1891

FirstthioaldehydeS-oxide•  Zwaneburgandcoworkersengineeredastablearoma1cbackbonethat

wouldprovidecrystallineproduct,aidinginisola1on

•  Obtainedin18%yieldasabrightyellowsolidamerrecrystalliza1onfromdichloromethane

•  Notablecharacteris1cinfraredbandsat1025and1145cm-1•  Protonα-tothethioaldehydeS-oxidehadchemicalshim(δ)9.47ppm

(upfieldofarylthioaldehydealphaprotons,ca.13ppm)•  DecomposedtoaldehydeandsulfuronexposuretoUVlight

OCH3

S Et3N

benzene, 0 ºC OCH3

SCl

O OH

Stra1ng,J.,Thijs,L.,Zwaneburg,B.Recl.Trav.Chim.Pays-Bas.1964,83,631

AlliumPhytochemistryandtheOnionLachrymatoryFactor

•  Anhistoricalprimer:–  1844:TheodorWertheim

isolates“allylschwefel”–  1857:CahoursandHofmann

reportsynthesisof“garlicoil”fromallyliodideandpotassiumsulfide

–  1891:Semmlerisolatesdiallyldisulfidebyfrac1onaldis1lla1onofgarlicoilat16mmHg

–  1944:Cavallitoisolatesallicinbycarefulextrac1onwithethanolandevapora1onbelow50ºC(6gfrom4kggarlic)

I K2S SEtOH

+

SS

SS

O

Block,E.GarlicandOtherAlliums:TheLoreandtheScience;RSC:London,2010

AlliumPhytochemistryandtheOnionLachrymatoryFactor

•  Cavallitonotedthatnoallicinorallylsulfidesweredetectedifthegarlicwaspulverizedandextractedat-70ºC

•  Preparedallicinbyoxida1onofdiallyldisulfide

•  Notedthatallicinformeddisulfideswithcysteine

SS

PhCO3H

63%SS

O

SS

O HSCO2H

NH2 94%S

CO2H

NH2

S+ 2 2

Block,E.GarlicandOtherAlliums:TheLoreandtheScience;RSC:London,2010

TowardstheOnionLF•  1949:StollandSeebeckisolatealliin,theprecursortoallicinbycold

extrac1on,concentra1onandcrystalliza1on,andsoonameriden1fytheenzymethatreleasesallicin

•  1961:VirtanenisolatesisoalliinasthecrystallineprecursortoonionLF

(129mgfrom5kgfreshonions)

S(S)(S)

O

(R)(R) NH2

CO2H

alliin(+)-allyl-L-cysteine sulfoxide

alliinaseS

H

O

self-condensation

SS

O

OOH

ONH3

SO

NH2

CO2H

isoalliinStoll,A.,Seebeck,E.Helv.Chim.Acta,1949,32,197Virtanen,A.I.,Spåre,C.–G.,SuomenKemisPl.,B.,1961,34,72

IsoalliinandtheOnionLF•  Sameenzyme,newsubstrate

–  VirtanenincorrectlyproposedpropylsulfenicacidfortheLFstructure•  WilkensusedstrongIRabsorp1onat1113and1144cm-1andtheabsence

ofC=C,O–H,S–Hbandsasjus1fica1onfortheS-oxide–  Alsonoteddimeriza1onanddecomposi1onweretypicalforsulfines

SO

NH2

CO2H

isoalliin

alliinaseSO

onion LFethylsulfine

SO S

OO

SSO

O

Wilkens,W.F.CornellUniv.Agr.Exp.StaPonMem.1964,No.385

TheForma1onofEthylSulfine

•  Notably,chemicalmethodstowardsethylsulfineprovideasimilarE/Zra1otowhatisseenenzyma1cally

•  ResearchbyBlockandcoworkersestablishedthattheZisomersofaldehydesulfinesaremorestableingeneral

SCl

O Et3N

Cl3CF, -20 ºC SO

Z/E 97:3

SO

NH2

CO2H alliinase

D2OH3C

DS

H

O

Z/E 95:5

SO

D

Block,E.,Penn,R.E.,Bazzi,A.A.,Cremer,D.TetrahedronLe:.1981,22,29

GeometryandGeneralSpectralCharacteris1cs

•  CSOsymmetricandan1symmetricstretchesareobservableat~1000and~1110respec1vely

•  UVabsorp1onofisolatedCSOisobservedatabout270nm

Bond Angle

C–H1 1.077Å ∠H1CH2 121.8±0.04º

C–H2 1.085Å ∠H1CS 115.6±0.10º

C=S 1.610Å ∠H2CS 122.5±0.08º

S=O 1.469Å ∠CSO 114.7±0.04º

H1 S

H2

O

Block,E.,Penn,R.E.,Olsen,R.J.,Sherwin,P.F.J.Am.Chem.Soc.1976,98,1264.Dataobtainedbymicrowavespectroscopyofatom-by-atomsubs1tu1onsofsulfinewithheavyisotopes.PreparedbyFVP.

E/Zisomerism•  KingandDurstfoundsulfinestoformgeometricalisomers

•  Dis1nguishedbytheirdifferentdipolemoments–  Z:3.97D–  E:2.63D

•  Isomeriza1ontothemorestableZisomertook8hoursinrefluxingCCl4•  Interconversionbarriersvary,∆G‡~33kcal/molfordiarylsulfines,lessthan

sulfoxidesat~37kcal/mol

King,J.F.,Durst,T.J.Am.Chem.Soc.1963,85,2676Ammon,R.,Berninger,H.,Haas,H.J.,Landsberg,I.Arzneim.Forsch.,1967,17,521

Cl

SO

Cl

SO

(E)-chlorophenylsulfinemp 5 ºC

(Z)-chlorophenylsulfinemp 39 ºC

E/Zisomerism•  1HNMRofortho-protonsareshimed~0.6ppmdownfieldinE

phenylsulfinescomparedtoZ•  Isomersareo\enseparablebycolumnchromatography

•  Kan1/synvariedbetween1.5and5.0dependingonarylsubs1tuents•  Isomeriza1onratewasobservedby1HNMRat110-180ºCandthebarrier

(∆G‡)wasfoundtobeinsensi1vetosolvent,temperatureoraddi1onalsubs1tu1ononthearoma1cring

SCH3O

SO

CH3

mp 59-60 ºCδMe = 2.14 ppm

mp 81-82 ºCδMe = 2.24 ppm

Bonini,B.F.,Lunazzi,L.,Maccagniani,G.,Mazzan1,G.J.Chem.Soc.Perkin1,1973,2314

StructuralDiversity•  Rejuvenatedinterestinsulfinesledtonewmethodologiestopreparea

largevarietyofC=S=Ocompoundsoverthelastfivedecades

R1 S

NR1R2

OR1HN S

NHR2

OR1S S

R2

OR1O S

R2

OS

NHR2

OO

R1

S

SSO

Cl S

ClO

PhS S

ClO

H3C

OSH3CO

t-Bu t-Bu

SSO S

OO

SO

R

Ph

PhPh

Ph

S O

CommonPrepara1onsThereareafewimportantmethodsprovidingsulfines:

–  Elimina1onofsulfinylhalides–  Oxida1onofthiocarbonyls–  Rearrangementofsulfoxidesandothersulfinylcompounds–  Addi1on/elimina1onwiththionylchloride–  Alkylidena1onofsulfurdioxide

Elimina1onofSulfinylHalides•  Thefirstmethodusedtopreparestablesulfines•  MoresuitabletoalkylthioaldehydeandthioketoneS-oxides,astheir

precursorsulfinylhalidesaremorestable,easilyprepared

t-Bu

t-Bu

SO

Clt-Bu

t-Bu

SO

-30 ºC100%

Pyridine

Buter,J.,Kellogg,R.M.J.Org.Chem.,1977,42,973(partoftheadventuretowardstetra-t-butylethylene)Block,E.,Revelle,L.K.,Bazzi,A.A.,TetrahedronLe:.1980,1277Carpino,L.A.,Williams,J.R.J.Org.Chem.1979,44,1177

R SOClEt3N

CCl3F, -20 ºCR S

O

HR = Me, Et, iPr, tBu

H3C S

ClCl

Cl2 1 equivAc2O 1 equiv

-30 ºC65%

H3C S

ClCl

O

Et3N 1 equiv

hexane, -30 ºCH3C S

Cl

O

Cl2 1.25 equiv

-30 ºC50%

H3C S

ClClCl

O

Oxida1onofThiocarbonyls•  Providesthelargestvarietyofsulfines•  Firstappliedinhydrogenperoxideoxida1onsofthioamides

•  TheN–H–O=Shydrogenbondpurportedlyhasasignificantstabilizingeffectallowingforgenerallylong-livedproducts

SH2N

H

H2O2H2O

SHN

H

OH28%

NHH3C

O

H2N S

H2O2MeOH

NHH3C

O

HN SOH

80%

Walter,W.,Curts,J.Chem.Ber.,1960,93,1511Walter,W.,Bode,K.D.,JustusLiebigsAnn.Chem.1962,660,74

H2N

O

S

NH2H2O2DMF

H2N

O

S

HN

O

H 66%

Oxida1onofThioketones•  Treatmentwithhydrogenperoxideyieldsonlyketone•  Simplyswitchingtoanyperacid(mCPBA,perphthalic,perace1cacids)

providessulfinenearinstantaneouslywithcarefulcontrolofstoichiometry

•  Enethiolizablesubstratesomenyieldonlydisulfide

S mCPBA SO 75%

SDMDO

S O

98%

Ph

S

SPh

monoperphthalicacid

Ph

S

SPh

100%E/Z 5:1

O

Zwanenburg,B.,Wagenaar,A.,Thijs,L.,Stra1ng,J.J.Chem.Soc.,PerkinTrans.11973,73Philipse,H.J.F.,Thesis,UniversityofNijmegen,TheNetherlands,1974Zwanenburg,B.,Thijs,L.,Stra1ng,J.,Recl.Trav.Chim.Pays-Bas,1971,90,614

Addi1on/Elimina1onswithThionylChloride

MeO2C

CO2MeSOCl2 (1 equiv)Et3N (2 equiv)

Et2O, -50 ºC to rt98%

MeO2C

CO2Me

SO

MeO

OTMSR

SOCl2 (1 equiv)Et3N or DIEA (1 equiv)

Et2O or CH2Cl2, -78 ºCMeO

OR

S O

MeO

O

S O

Me

Me

MeO

O

S O

Ph MeO

O

S O

Ph

Me

MeO

OPh

S O

MeO

OOMe

S O

MeO

OOPh

S O

89% 93% 84% 96% 93% 97%

Zwanenburg,B.ThioaldehydeandThioketone–Oxidesand–Imides(SulfinesandDeriva1ves).ScienceofSynthesis,ver.4.0;GeorgThiemeVerlag:StuRgart,2014.

Alkylidena1onofSulfurDioxide

Ph Ph

PPh3 SO2 (1 atm)

benzene, rt50%

Ph Ph

SO

Zwanenburg,B.,Venier,C.G.,Porskamp,P.A.T.W.vanderLeij,M.TetrahedronLe:.1978,807

P PhO

EtO OEt

1) BuLi, -78 ºC

2) TMSCl P PhO

EtO OEt

TMS 1) BuLi, -78 ºC

2) SO2, -78 ºC P PhO

EtO OEt

0 ºC

-OTMS

STMS OO

P PhO

EtO OEt

S O

one pot65%

Alkylidena1onofSulfurDioxide

TMS

TMS

1) BuLi

2) PhCHO

TMS

Ph

1) MeLi

2) SO2

S

PhMe

O

one pot64%

Canbemadevinylogous,providingα,β-unsaturatedsulfines

Nucleophilicaddi1ontovinylsilanesprovidedα-methylenesulfines,problema1ctopreparebyoxida1on

SO2Ph

TMS PhLi

-78 ºC SO2Ph

TMSPh

SO2

SO2Ph

SPh

O72%

VanderLeij,M.,Zwanenburg,B.,TetrahedronLe:.,1978,3383Porskamp,P.A.T.W.,vanderLeij,M.,Lammerink,B.M.H.,Zwanenburg,B.Recl.Trav.Chim.Pays-Bas,1983,102,506

Forma1onbyRearrangementS

13:87 at 23 ºC

S

SOS

>99:1 at 23 ºC

96%

OS mCPBA

Hwu,J.R.,Anderson,D.A.J.Chem.Soc.Perkin1,1991,3199Porskamp,P.A.T.W.,Lammerink,B.H.M.,Zwanenburg,B.J.Org.Chem.1984,49,263-268

R1

SR2

R3

mCPBA, -20 ºCwarm to -7 ºC R1 R3R2

CHSO

MeMe

CHSO CHSO

Cl

92% 81% 90%

SO

Forma1onbyRearrangementMgBrMe MeO

Me

S

Me

O

THF

-78 ºC, 30 min+

Me

S

Me

OMe NH4Cl, H2O

-78 ºC to rt

SMeO

Me Me

50%E/Z 60:40

Baudin,J.B.,Commenil,M.–G.,Julia,S.A.,Wang,Y.Synle:,1992,909

n-Bu

SO

OMeMe

MgBrTHF

-78 ºC, 30 min

NH4Cl, H2O

to rt+ O

S H

n-Bu

Me

67%E/Z 5:95

C

SO

OMe MgBrTHF

-78 ºC, 30 min

NH4Cl, H2O

to rt

OS Me

80%E/Z 100:0

Me MeMe

MeMe

Me

Me

Me

Me

Reac1onsofSulfines

•  Thiophilicaddi1ons•  1,3-dipolarcycloaddi1ons– Sulfineasdipolarophile

– Sulfineasdipole•  [4+2]cycloaddi1ons

SO 1) Nu-

2) E+

SO Nu

E

SO

C BA S

O

CB

A+

SO

AB SO

AB

+

SO SO

+

ThiophilicAddi1ons

MeO

OPh

S O

nBuLi

THF, -78 ºC96%, only product

dr 2:3

MeO

OPh

SOn-Bu

MeO

OPh

SOn-Bu

+

Damen,T.J.G.,Thesis,UniversityofNijmegen,TheNetherlands,2002.Porskamp,P.A.T.W.,Lammerink,B.M.H.,Zwanenburg,B.J.Org.Chem.,1984,49,263

P PhO

EtO OEt

S OMeLi

THF, -78 ºC92%

P PhO

EtO OEt

SOMe

1) nBuLi

2) PhCHO88%

Ph

SOMe

Ph

E/Z mixtureno ratio given

Thiophilicvs.Carbophilic

Me

SPh

SO1) MeLi

2) MeIMe

SO

MeSPh

Me

Veenstra,G.E.,Zwanenburg,B.,Tetrahedron,1978,34,1585VanderLeij,M.,Zwanenburg,B.,Recl.Trav.Chim.Pays-Bas,1980,99,49

OLi

Me

SPh

SOO S

MeOMeI workup

+90%

OLi1) TolC(SO)SPh

2) BrCH2CO2Et54%

SOEtO2C

p-Tol

GroupProblem

PhO2S SO

PhH2C

N2N

S

NSO2Ph

Ph+

2 d, 0 ºCbenzene/ether 4:1

0 ºC, 5 min 56%

Provideamechanismforthefollowingreac1on

PhO2S SO

PhH2C

N2N

S

NSO2Ph

Ph+

2 d, 0 ºCbenzene/ether 4:1

0 ºC, 5 min 56%

N

S

N

O

PhPhO2S

N

S

N

O

PhPhO2S

HN

S

N

O

PhPhO2S -PhSO2H

N

S

N

OPh

PhSO2H N

S

HN

OPh

SO2Ph-H2O

N

S

N

OPh

SO2Ph N

S

N

PhSO2Ph

Zwanenburg,B.,Wagenaar,A.TetrahedronLe:.1973,5009

Crossoverexperimentwithtwodifferentlysubs1tutedsulfonylgroupsprovidedevidencefordisplacementandreincorpora1onofsulfinate,althoughanintramolecularmechanismwassuggested

SulfineasDipolarophile

R1 R2

SO N2Et2O or CH2Cl2

-30 ºC

N

S

N

O

R2R1

+

N

S

N

O

PhCl

81%from E-sulfine

N

S

N

O

ClPh

56%from Z-sulfine

Thijs,L.,Wagenaar,A.,vanRens,E.M.M.,Zwaneburg,B.TetrahedronLe:.1973,3589

Ph Ph

SO NPh

ClOH Et3N

Et2O, 20 ºC80%

+ S

ON

PhO

PhPh

SulfineasDipole

O

S O

Ph Ph

S CH2Cl2

rt, 12 h62% O

SOS

PhPh

+

N Ph

Ph Ph

S O BF3-OEt2 (1 equiv)

Et2O, 20 ºC, 1 h70%

+

OS

N

PhPh

toluene

reflux, 10 h65% N

SO

PhPh

Thijs,L.,Wagenaar,A.,vanRens,E.M.M.,Zwaneburg,B.TetrahedronLe:.1973,3589Bonini,B.F.,Maccagnani,G.,Mazzan1,G.,Zwanenburg,B.J.Chem.Soc.,Chem.Commun.,1985,237

Bothreac1onshaveverylimitedscope,butillustratetheambiphilicnatureofthefunc1onalgroup

Diels-AlderReac1ons

R1

S

CO2Me

O

R2

R2

SnCl4SR2

R2

CO2MeR1

O

+

SAcO

OAc

CO2MeMe

O

CH2Cl2, -25 ºC1 h

S CO2MeMe

OS CO2Me

Ph

O

82% 96% 88%

S O

neat, reflux30 min

75%

SO

Zwanenburg,B.,Thijs,L.,Broens,J.B.,Stra1ng,J.Recl.Trav.Chim.Pays-Bas,1972,91,443Zwanenburg,B.,Damen,T.J.G.,Philipse,H.J.F.,deLaet,R.C.,Lucassen,A.C.B.Phosphorus,SulfurSiliconRelat.Elem.1999,153/154,119

Zwiebelanes:TheMissing“Dimer”S

S

O

Allicin

SS

O

LF condensationproduct?

SS

mCPBA

Na2CO3-60 ºC

SS

O 0 ºC

S

S

O

S

SO

[3,3]

S

SO

[2+2]

Thebicyclicsulfide-sulfoxide,trans-Zwiebelane,wasisolatedfromonionsbyBlockin1996andsubsequentlysynthesized

S

S

OS

S

O

Zwiebelanes

ChemistryintheFryingPan

•  Combininggarlic,onionandproteincanleadtosurprising(perhapsunappe1zing)colors

BlueGarlic/OnionMixturesReac1onofmixedgarlicandonionthiosulfinateswithaminoacidsgivesalargerangeofcolors1)Cys2)Phe3)Gly4)Met5)Arg6)Val7)Ile8)Pro9)Lys10)Ser11)Trp12)h-Pro13)Ala14)Asp15)His16)Thr17)Leu18)Asn19)Gln20)Cyt21)Glu22)Tyr23)mixture

NN

CO2HRR CO2H

λmax 570 nmCho,J.,Lee,E.J.,Yoo,K.S.,Lee,S.K.,Pa1l,B.S.,J.Food.Sci.,2009,74,C11

BlueGarlic/OnionMixtures

NN

CO2HRR CO2H

λmax 570 nmCho,J.,Lee,E.J.,Yoo,K.S.,Lee,S.K.,Pa1l,B.S.,J.Food.Sci.,2009,74,C11

N

RCO2H

N

CO2HR

+

SSO

SSO

[3,3] HO2C R

NH2

N

RCO2H

SSOH

EiSOH S+

N

CO2HRSH

N

CO2HR-H2S

Onion“Pinking”•  Drums1ckonions(Alliumrosenorumandothers)produceadeepred

pigmentuponhea1ngor1ssuedamage

•  Theseonionswerefoundtocontainanunusualcysteinesulfoxide

Jedelska,J.,Vogt,A.,Reinscheid,U.M.,Kuesgen,M.J.Agric.FoodChem.2008,56,1465

HN

SO CO2H

NH2

OnionPinking

NH

SO

HO2C NH2

alliinase

NH

S OHcondensation

NH

S SO

NH

[3,3]

NH

S S

NH

O

NH

SHS

NH

HOcondensation

NH

S S

NH

red pigment

References

•  Reviewsonsulfines:– Zwanenburg,B.Recl.Trav.Chim.Pays-Bas,1982,101,1

– Zwanenburg,B.J.SulfurChem.2013,34,142

•  AlliumChemistry:– Block,E.GarlicandOtherAlliums:TheLoreandtheScience;RSC:London,2010