Selected Reactions of Thiocarbonyl Compounds Oac O Ncy Oac CN 2 Shyam Krishnan Me Meo Monday, June 12, 2006 Me H Me N O H 8 P.M

OH S Me S O O N SEt TBSO Ph O Me Me N OH BnO S

Selected Reactions of Thiocarbonyl Compounds OAc O NCy OAc CN 2 Shyam Krishnan Me MeO Monday, June 12, 2006 Me H Me N O H 8 p.m. N O Me 147 Noyes H O O O HN O H H S Me S S H H BnO BnO

N N i) ICH2CO2Et, CHCl3

S ii) PPh , DABCO, 3 CO2Et CHCl3, reflux (92% yield) I I OMe OMe Selected Reactions of Thiocarbonyl Compounds

1) Thiocarbonyl compounds: nomenclature and structural properties

2) Methods of Synthesis

3) Reactions of thiocarbonyl compounds and their application in the synthesis of functionalized molecules 1) Reactions of carbanions derived from Thiocarbonyl compounds. 2) Carbanion addition to the thiocarbonyl group. 3) Reactions with electrophiles - the Eschenmoser sulfide contraction. 4) Radical mediated reactions. 5) [3,3] sigmatropic rearrangements - the thio-Claisen rearrangement. 6) [4+2] cycloaddition reactions. 7) [3+2] Dipolar cycloadditions. 8) Summary and future directions.

Reviews:

General review: Metzner, P. Top. Curr. Chem. 1999, 204, 127. General review: Metzner, P. Synthesis 1992, 1185. Synthesis of heterocycles: Jagodzinski, T.S. Chem. Rev. 2003, 103, 197. Radical chemistry: Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413. Photochemistry: Coyle, J. D. Tetrahedron 1985, 41, 5393. Thiocarbonyl Compounds Structures, Nomenclature and Stability

Thiocarbonyl compounds possess a carbon-sulfur double bond

Thiocarbonyl compounds with at least one organic group bound to the thiocarbonyl carbon:

O S S S S S S

R H R R' R OR R NR2 R SR R R'

Thioaldehyde Thioketone Thionoester Thioamide Dithioester Sulfine/Thiocarbonyl oxide

Typically display greater reactivity than their carbonyl (oxygen) analogs

• Larger covalent radius of sulfur vs oxygen (104.9 nm vs 70.2 nm), less efficient overlap in S3p-C2p π-bond

• Dissociation energy of C=S (115 kcal/mol) is significantly lower than for C=O (162 kcal/mol).

• Higher Polarisability of sulfur relative to oxygen

• Sulfines/thiocarbonyl oxides do not have stable counterparts among their oxygen analogs.

• Thioaldehydes and many thioketones are very reactive towards dimer, trimer or oligomer formation; often need to be generated in situ. Thiocarbonyl Compounds Spectroscopic Features

UV-vis spectroscopy: Many thiocarbonyl compounds are colored! This is likely due to an n π* transition S S S H Me Bn Ph S

O Me

λmax 575 nm 592 nm 697 nm 569 nm

IR spectroscopy: C=S stretching vibration is only of medium intensity, 1100-1300 cm-1 . Enethiols absorb around 2550 cm-1 (SH) and 1640 cm-1 (C=C).

13C NMR: The thiocarbonyl carbon appears 35-63 ppm downfield relative to the carbonyl analog! Me S S Me S S Me Me Me Me Me Me Me Me S Me H S Me Me Me Me

δ(C=S) 279.8 289.1 245.2, 267.7 255.6

Chemical shift ~ 200 ppm for thioamide C=S Schaumann, E. in Supplement A, The Chemistry of double-bonded functional groups. Patai, S. (ed.), 1989, Vol 2. Part 2, p. 1269 Thiocarbonyl Compounds Thial/Thione - Ene-thiol tautomerism

The enethiol tautomer is favored to a greater extent than in keto-enol tautomerism

CCl4

S SH 40 ºC 42% 58%

CCl4

S 40 ºC SH 47% 53%

Paquer, D. et al. J. Bull. Soc. Chim. Fr. 1971, 4407 However, calculations on butane-2-thione suggest a high kinetic barrier to interconversion (85 kcalmol-1) Thione and ene-thiol tautomers can be separated by GC (Lipscomb, R.D. et al, J. Polym. Sci. Part 1 1970, 8, 2187).

Ar Ar Keq Ph Ph S SH Ph Ph

Ar = Ph, p-OMeC6H4

No thioketone observable even after 2 weeks of attempted equilibration 6 Authors estimate Keq ≥ 10 times that for the corresponding oxygen analogs! Rappoport, Z. and co-workers, J. Org. Chem. 1996, 61, 5462. Thiocarbonyl Compounds Synthesis Routes

Most generally-applicable route: thionation of the corresponding carbonyl compound:

O S thionation R X R X R= alkyl, aryl. X = alkyl, aryl, H, OR, NR2, SR.

Commonly used thionation reagents: R S P S P4S10 S P R S

R = p-OMe-Ph (Lawesson's reagent) SMe (Davy reagent) PhOPh (Belleau reagent)

For a review of thionation using Lawesson's reagent: Jesberger, M. et al. Synthesis 2003, 13, 1929.

S S 2 3 S CS2 BtSO2CF3 R R NH R1MgX 1 R1 N 1 2 3 THF R SMgX THF, 20 ºC THF, 65 ºC R NR R N (Bt = benzotriazole) N 45-79% yield

Katritzky, A.R., and co-workers, Synthesis 1995, 1497. Thiocarbonyl Compounds Synthesis Routes

Photolysis of phenacyl thioethers: R H H X O X X O hν S R S Ph S R Ph X = aryl, alkyl, H, OR R = aryl, alkyl

Mild conditions for formation of non-enethiolizable thioketones and thioaldehydes:

O Me3Si-S-SiMe3 (1-2 equiv.) S

R1 R2 TMSOTf (20 mol%) OR R1 R2 CoCl2.6H2O (20 mol%) MeCN, 20 ºC Thioaldehydes were generated in the presence of a trapping agent (diene) Degl'Innocenti, A., and co-workers, J. Org. Chem. 1991, 56, 7323.

For enethiolizable thioketones:

MeO OMe S H2S, cat. ZnCl2 R1 R1 R3 R3 EtOH or THF, 0 ºC, 30 min R2 R2 36-67% yields

Authors were able to isolate thioketones free from enethiols. Metzner, P., and co-workers. Tetrahedron Lett. 1992, 33, 6151. Thiocarbonyl Compounds Synthesis Routes for Sulfines

Peracid oxidation of thiocarbonyl compounds:

O S S 1 m-CPBA R 1 X R CH Cl , 0 ºC X 2 2 2 R R2 X = SR, OR, alkyl, aryl R1, R2 = alkyl, aryl Metzner, P., and co-workers, Tetrahedron Lett. 1991, 32, 747.

[3,3]-sigmatropic rearrangement of vinyl allyl sulfoxides:

O R2 O 2 R3 S R O R3 S Z 3 OMe + R MgBr S R3 H THF, -78 ºC 1 1 3 R R2 R1 R R R3 Z:E > 95:5 R2 = Me, H R1 = Alkyl 65-71% yields R3 = Me, H

Reactions to form thioketone-S-oxides are less stereoselective Baudin, J-B., et al Synlett 1992, 909. Aldol Reaction and Thiophilic Addition to Dithioesters The Meyers approach to Maysine

O SLi OH S OEt O O i) cat. p-TsOH, Et2O, 0 ºC to rt SEt TBSO H TBSO SEt Me Me THF/Hexane Me Me -120 ºC ii) EtMgI, Et2O, -25 ºC dr 10:1, 62% yield of desired diastereomer

O OEE SEt EEO EtS SEt O MgI N N H O SEt Me H TBSO TBSO Et O, -25 ºC Me Me 2 Me Me O (67% yield, 3 steps)

Cl Me O O Me MeO N • Ester enolates result in poor dr in the aldol reaction. • Reaction at -78 ºC yields only 3:1 dr. Me O

N O H Me MeO HO

(−)-Maysine Meyers, A.I., and co-workers, J. Am. Chem. Soc. 1983, 105, 5015. Michael Addition of Thioamide Enolates The Heathcock approach to Methyl Homodaphniphyllate

OBn OBn O O O + − i) LDA, THF O Et3O BF4 O Me N Me N O 2,6-DTBP N -78 ºC S CHCl3, rt ii) O O O SEt BnO S Me Me Me Me ( 83% yield, 5:1 dr)

OBn CO2Me O Me Et3N Me O H N Me CHCl3, reflux, 2d N (80% yield, single diastereomer) O (±)-Methyl Homodaphniphyllate

• The enolate of the corresponding amide reacts predominantly 1,2-fashion. • Major diastereomer undergoes efficient cyclization.

Heathcock, C.H., and co-workers, J. Org. Chem. 1992, 57, 2531-2534. Deprotonation of Acyl Thioamides Synthesis of β-lactams

S S S PhCO Me LDA LDA, THF 2 O Me2N Me2N H -100 ºC Me2N Li (68 % yield) THF, -100 ºC Ph

Li Me S O Me O S N 3 N MeN Ph Ph (81 % yield) (62 % yield) Ph OH OH O

Other substituted benzoate esters can be used, as well as non-enolizable esters.

Creary, X., and co-workers, J. Am. Chem. Soc. 1995, 117, 5859. Addition of Nucleophiles to Thionolactones Synthesis of Medium-ring Ethers

S Nu MeS Nu − O i) Nu , THF, -78 ºC O Ph3SnH, AIBN (cat.) O

ii) MeI, -78 ºC to 0 ºC Toluene, 110 ºC (82-92% yield)

High yields of addition products with organolithium reagents ( 79-92% yield). Organomagnesium reagents (except allyl magnesium bromide) react poorly.

Reduction of the mixed thioketal is frequently highly diastereoselective:

i) EtLi, THF, -78 ºC Me Me O 5 ii)MeI, -78 ºC to 0 ºC O 5 iii) Ph SnH, AIBN (cat.), S 3 Me Toluene, 100 ºC (80 % overall yield) (±)-lauthisan

Nicolaou, K.C., and co-workers, J. Am. Chem. Soc. 1990, 112, 6263. Addition of Nucleophiles to Thionolactones Synthesis of Polyethers

Me Me Me H Me Me H Me O n O 1. Bu3SnLi, THF, -78 ºC

2. MeI O O O O SnBu3 H H S Bu Sn H H S 3 SMe SMe

3. Cu(OTf)2, pempidine (45 % yield overall)

Me Me Me Me H Me Me H O 1. n-BuLi, THF, -78 ºC O

OBn 2. BnO O O O OTf O H H BnO H H SnBu3 HMPA, Et3N, THF, -78 ºC Bu3Sn (65% yield)

Nicolaou, K.C., and co-workers. J. Am. Chem. Soc. 1990, 112, 3696. Addition of Nucleophiles to Thionolactones Synthesis of Polyethers

OBn OBn Me H Me H TBSO(CH ) (2-thienyl)CuCNLi , O O 2 4 2 Et2O, -78 ºC to 10 ºC; then OBn O OBn I(CH ) I, pempidine O O 2 4 S H H O (85% yield) S H H OTBS

OBn OBn Me H Me H O O HO BH .THF, THF, 0 ºC; then OBn 3 OBn O O O O H H H O , NaOH H H H 2 2 (89% yield)

OTBS OTBS

Nicolaou, K.C., and co-workers: J. Am. Chem. Soc. 1993, 115, 3558. J. Am. Chem. Soc. 1992, 114, 7935. J. Am. Chem. Soc. 1990, 112, 4988. Brevetoxins Eschenmoser Sulfide contraction Synthesis of vinylogous amides, urethanes and amidines Via initial alkylation on the thioamide: Br

R S R S O S X O Base, X R S R N N X H R' R' O X phosphine N NH O R' R' X = R, OR H

R R R X − S=PR3 N NHR NH O R' R' (for X = R)

R Via initial oxidation of the thioamide: HN R R X R S S R S R P R (BzO)2 R S O 3 N R R N R' HN NH N N O H R' R' R R' O R R − S=PR3 N NHR R' Eschemoser, A., and co-workers, Angew. Chem. Intl. Ed. Engl. 1973, 12, 910. For a review, see Shiosaki, K. in Comprehensive Organic Synthesis, Trost, B.M., Fleming, I., Eds., Pergamon Press, Oxford, Vol.2. 865. Eschenmoser Sulfide Contraction Application in Synthesis of the Lythrancepines II & III

H H H BnO BnO BnO

N N NaCNBH3, pH 4 N i) ICH2CO2Et, CHCl3 MeOH/THF, 25 ºC S ii) PPh , DABCO, 3 CO2Et (8.8:1 dr, CO2Et CHCl3, reflux 98% combined yield) I (92% yield) I I OMe OMe OMe

H RO

N OAc

OMe MeO R = H, Lythrancepine II R = Ac, Lythrancepine III

Hart, D.A., and co-workers, J. Org. Chem. 1987, 52, 4665. Eschenmoser Sulfide Contraction Synthesis of the Lythrancepines - a more convergent approach fails H OMe BnO H AcO Br I N N O O S then PPh3, DABCO, CHCl3, reflux I I OMe OMe I OMe

H H BnO BnO

N O N (− H O) S 2 S (68 % yield) I I OMe OMe OMe I

I OMe

Hart, D.A., and co-workers, J. Org. Chem. 1987, 52, 4665. Eschenmoser Sulfide Contraction Application in Semicorrin synthesis

S O S 2 TrO (PhCOO) TrO NH TrO 2 N Me + NH Me Me PhH, 0 ºC to rt TrO NC Me TrO NC Me

6:1 dr TrO

TrO TrO TrO

P(OEt)3, PhH S 3 OTr Me OTr Me Me (56 % yield) 120 ºC (90% combined yield)TrO TrO N N NC HN HN Me NC Me Me O O OTr 36:6:6:1 ratio of diastereomers (epimerization at C-3) 67% yield of desired semicorrin after prep. HPLC

Mulzer, J., and co-workers, J. Am. Chem. Soc. 1997, 119, 5512. Reactions via Radical Intermediates Synthesis of Kainic Acid

SEt SEt Me SEt Me nBu SnH, AIBN, i) H2S, DBU, F3CCH2OH, rt 3 Toluene, 100 ºC OTMS Me ii) TMSCl, HMDS, CH2Cl2, rt OTMS H S O t CO2 Bu iii) Boc2O, 4-DMAP, THF, rt then TBAF, AcOH t t Bu3SnS N CO2 Bu N (60% yield) H N CO2 Bu THF, rt Boc Boc (73% yield)

OH CO H OH 2 Me Me t Me CO2 Bu t CO H CO2 Bu 2 N N Bu3SnS Boc N Boc H (−)-Kainic Acid

Bachi, M.D., and co-workers, J. Org. Chem. 1997, 62, 1896. Reactions via Radical Intermediates The Fukuyama Synthesis of Indoles - Application to the Synthesis of Strychnine

i) CSCl , Na CO TBSO 2 2 3 TBSO n THF/H O, 0 ºC Bu3SnH, Et3B 2 MeO2C CO2Me S NaH, THF Toluene, rt ii) NaBH4, MeOH, 0 ºC S 0 ºC to rt CO2Me N iii) TBSCl, Im, CH2Cl2, rt C N (52% yield) (55% overall yield) N (71% yield) H CO2Me

OTBS TBSO OTBS Bu3Sn SSnBu3 CO Me CO2Me 2 CO2Me N H N N CO2Me CO2Me H CO2Me

H N H O O H Strychnine

Fukuyama, T., and co-workers, J. Am. Chem. Soc. 2004, 126, 10246. Transannular Bis-Thionolactone Cyclization Synthesis of Polyethers

H H O 1. Lawesson's reagent, toluene, reflux MeS O H O H O (78% yield) O

O 2. Sodium naphthalenide, THF, -78 ºC; O then MeI, -78 ºC to 25 ºC H O O O SMe H (80% yield) H

n H H Bu3SnH, AIBN H O O O H Toluene, reflux HMeS AgBF , Et SiH, O (99% yield) O 4 3 H H CH2Cl2, 25 ºC O O O O H H H OR H (95% yield) O O SMe H hν, toluene, 25 ºC H O (99% yield) H

Nicolaou, K.C., and co-workers: J. Am. Chem. Soc. 1986, 108, 6800. J. Am. Chem. Soc. 1990, 112, 3040. Transannular Bis-Thionolactone Cyclization Synthesis of Polyethers

H H O O H S H S O O hν S O O Toluene, 25 ºC H O S (65 % yield) O H H First isolated dithietane "dithiatopazine" ("yellow-orange topaz-like crystals")

O H H O Ph3P H H O O H S CH2Cl2, 25 ºC O + O S H O O H H (46% yield) (45% yield)

m-CPBA, CH Cl , 25 ºC O3, CH2Cl2, -78 ºC 2 2 O (55% yield) then Me2S, -78 ºC to H 25 ºC (85% yield) H O H O O O H

Nicolaou, K.C., and co-workers. J. Am. Chem. Soc. 1990, 112, 3029. Desulfurization of Thioamides Applications in alkaloid synthesis

Me Me O

i) P4S10, THF (76% yield) N N H H ii) Raney-Ni, THF (80% yield) H H

CO Me N CO2Me N 2 H H pseudovincadifformine

Szantay, C., and co-workers, J. Org. Chem. 1993, 58, 6076.

OH OAc O NCy2 OAc O O CN OAc CN NCy2 OAc CN MeO MeO i) Lawesson's N N MeO H H Reagent, PhH, 80 ºC N N N O (85% yield) H Me Me Me N O H H Me O N O HN O ii) Raney-Ni, Acetone, rt H Me (87 % yield) OMe N O O O Cyanocycline A

Fukuyama, T., and co-workers, J. Am. Chem. Soc. 1987, 109, 1587. Asymmetric Thio-Claisen Rearrangement Meyers' approach

MeO Me MeO Me MeO Me i) LDA, THF, -78 ºC O O O then MeI i) LDA, THF, 0 ºC N N Me N 1 Ph ii) Lawesson's reagent, Me ii) R Br Ph Ph S toluene, 110 ºC O S 2 (86% overall yield) R R2

Me 1 2 MeO Me MeO 1 R2 THF, 25 ºC (R = Me, R = H) 1 R OR O R [3,3] O R2 N N Me Me Xylene, 140 ºC (R1 = R2 = Me) Ph Ph S S

R1 = Me, R2 = H, 79% yield, 91:9 dr O R1 = R2 = Me, 68% yield, >99:1 dr.

+ − i) Et3O BF4 , 1,2-DCE, 83 ºC ii) Red-Al, 0 ºC; then HClO4, EtOH/H2O iii) KOH, MeOH, rt Me R Me R = H, 82% yield R = Me, 77% yield

Meyers, A.I., and co-workers, J. Am. Chem. Soc. 1994, 116, 2633 Asymmetric Thio-Claisen Rearrangement Use of C2−Symmetric Diamines as Chiral Auxilliaries

R2 1 R Ph S 1 2 Ph R R i) n-BuLi, THF, -78 ºC Ph R3 S [3,3] ii) R-X, conditions S N N 3 N Me R Me Ph Me Ph Ph

R-X Conditions Yield (%) dr Me S R2 Br -78 ºC to rt 98 9.8:1 R1 N Me -78 ºC to rt 100 7.7:1 Br Favored Me Br reflux, 6h 89 >200:1 Me Me R2 Br S 1 reflux, 6h 91 >100:1 R N

Disfavored

Rawal, V., and co-workers, J. Am. Chem. Soc. 2000, 122, 190. Asymmetric Thio-Claisen Rearrangement Use of C2−Symmetric Diamines as Chiral Auxilliaries

R2 1 R Ph S 1 2 Ph R R i) n-BuLi, THF, -78 ºC Ph S [3,3] ii) R-X, conditions S N N N Me Me Ph Me Ph Ph

R-X Conditions Yield (%) syn:anti dr Me

Me Br -78 ºC to rt 93 1:41 88:12 S R2 R1 Br N reflux, 3h 92 >30:1 >99:1 Me

Ph Br -78 ºC to rt 100 <1:100 83:17 Favored

Br reflux, 8h 86 >30:1 >99:1 Me 2 Ph R Br S Me reflux, 9h 81 <1:50 >99:1 R1 Me N Me Br reflux, 9h 88 >50:1 >99:1 Me Disfavored

Z-oriented substituent (i.e. R1) on allyl fragment results in higher dr. Rawal, V., and co-workers, J. Am. Chem. Soc. 2000, 122, 190. Diels-Alder Reactions Thiocarbonyl compounds as dienophiles: Vedejs' synthesis of Otonecine

OTMS OTMS Ph O OBn OBn

, hν [4+2] MeO S S OBn MeO S Bn PhH, rt Bn N N Boc Boc NBnBoc

O OBn i) L-selectride, THF, rt TFA, CH2Cl2 ii) NaH, BnBr, THF/DMF, rt SMe 0 ºC to rt iii) NaCNBH , CF CH OH/AcOH, rt BnN (82% yield, 2 steps) S 3 3 2 BnN OBn iv) MeI/DBU, PhH, rt (78% overall yield) OBn

OH OH O O MeN MeN OH OH Otonecine

Vedejs, E., and co-workers, J. Am. Chem. Soc. 1998, 120, 3613. Diels-Alder Reactions Thiocarbonyl compounds as heterodienes - an alternate glycosylation strategy O

Me N S Me Me O Cl HO O Pyridine O S S O O CH2Cl2, rt O NPhth CHCl3, rt Me 95% yield Me Me diacylthione BnO A BnO O BnO BnO S BnO O A O BnO Me Pyridine, CHCl3, rt (80% yield) O Me

O OBn OBn SNPhth O BnO BnO OBn O O BnO Me O BnO Raney-Ni BnO O S O O Me Pyridine, CHCl , rt 0 ºC → 25 ºC BnO 3 O O (43 % yield) PhH/Toluene (45% yield) O O

Me Desulfurization complicated by competing olefin reduction Capozzi, G., and co-workers, Angew. Chem. Intl. Ed. Engl. 1996, 35, 777. [3+2] Cycloadditions

Thiocarbonyl compounds function as excellent dipolarophiles in dipolar cycloadditions. However, applications in complex molecule syntheses have been limited thus far.

Synthesis of sterically-hindered olefins:

N2 Me t Me Me Me Me Bu Me t t Me Me Me Bu Bu S −N2 ring closure S tBu S THF, reflux N N tBu tBu Me Me Me Me t Me PBu3, 120 ºC Me Bu S tBu t then MeI, pet. ether Bu (64% overall yield) tBu

Barton, D.H.R., and co-workers, J. Chem. Soc. Perkin Trans.1 1974, 1794.

Formal synthesis of biotin: O O Cl S S Cl R1 S CH N , Et O R1 N O Cl MeO 2 2 2 SMe N O 2 -90 ºC to -60 ºC R S Cl -90 ºC O 2 O O R S (-N2) O O O

C 1 S HN3, pyridine EtOH R NHCO2Et HN NH R1 S N

CHCl3, -60 ºC to rt reflux 2 O R S NHCO Et HO C O R2S (67% yield 2 2 N C O overall) 4 S

Moran, J.R., and co-workers, Tetrahedron 1990, 46, 1057. Summary and Future Directions

1. Thiocarbonyl compounds display diverse reactivity towards nucleophiles, electrophiles, free radicals, sigmatropic rearrangements and cycloadditions.

2. They are often readily accessible from the corresponding carbonyl compounds (more familiar to organic chemists!), therefore reactivity can be readily evaluated in a bid to solve problems posed by complex molecule synthesis.

3. Future directions: Transition metal-catalyzed reactions, multi-component couplings.

When in doubt, bleach!