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