2,5-Dihydro-2,2-dimethyl-5,5-bis(propylthio)-1,3,4-oxadiazole

[222625-77-6]  · C10H20N2OS2  · (248.41)

(reagent used as bis(propylthio)carbene precursor)

Physical Data: solid at -78°C, thermolysis occurs at 0°C and above.

Solubility: hexanes, cyclohexane, dichloromethane, benzene, toluene, xylene.

Form Supplied in: colorless oil as synthesized.

Purification: column chromatography at 0°C using hexanes-ethyl acetate (20:1); product elutes first; collect fractions in an ice bath; remove solvent in vacuo at 0°C; dry under high vacuum at 0°C for 1 h.

Handling, Storage, and Precautions: to prevent premature thermolysis, reagent should be stored in a sealed flask in a cooler with dry ice at -78°C. Since the reagent is thermally labile and thermolysis is exothermic, avoid exposure to heat to prevent rapid evolution of nitrogen gas leading to a possible explosion. Thermolysis will occur at 0°C and above. Use of an explosion shield and slow addition to refluxing solvents are recommended.

[1+4] Cycloaddition with Vinyl Isocyanates

Upon thermolysis in refluxing benzene, 2,5-dihydro-2,2-dimethyl-5,5-bis(propylthio)-1,3,4-oxadiazole yields the bis(propylthio)carbene precursor, which reacts as a 1,1-dipole equivalent in [1+4] cycloaddition reactions with various vinyl isocyanate substrates leading to highly functionalized adducts such as hydroindolones (eq 1).1-3 Reductive desulfurization with Raney nickel yields the enamide or the fully reduced system (eq 2).1 Cyclohexyl isocyanide also behaves as a 1,1-dipole equivalent in [1+4] cycloadditions with vinyl isocyanates, however the adducts are less functionalized.4,5

Dimethoxy carbene has been shown to behave as a carbonyl 1,1-dipole equivalent in [1+4] cycloadditions with vinyl isocyanates also yielding functionalized adducts.6 However, the oxadiazole precursor requires higher thermolysis temperatures and hydrolysis of the acetals in the resultant adducts can be difficult for acid-sensitive systems.

[4+1+1] Cycloaddition with Vinyl Isocyanate

When a large excess of 2,5-dihydro-2,2-dimethyl-5,5-bis(propylthio)-1,3,4-oxadiazole carbene precursor is added rapidly in refluxing benzene to a vinyl isocyanate, two equivalents of carbene add to the substrate prior to ring closure, leading to a six-membered adduct (eq 3).1,2 However, no carbene insertion into the amide N-H bond occurs. This phenomenon is not observed with the dimethoxy carbene.2

Addition of Bis(propylthio)carbenes to Aryl Isocyanates

Addition of 2,5-dihydro-2,2-dimethyl-5,5-bis(propylthio)-1,3,4-oxadiazole in refluxing benzene and an aryl isocyanate releases the bis(propylthio)carbene in situ which then adds easily to the aryl isocyanate to yield a substituted isatin with the ketone functionality protected as a thioacetal (eq 4).7 Ring closure also occurred when the 2,5-dihydro-2,2-dimethyl-5,5-bis(propylthio)-1,3,4-oxadiazole carbene precursor was added to 1-naphthyl isocyanate in refluxing acetonitrile (eq 5).7 Formation of thioacetal protected isatin products are unique to the bis(propylthio)carbene as other nucleophilic carbenes added to aryl isocyanates afforded only modest yields of hydantoin products.8

Dimerization

Upon thermolysis of 2,5-dihydro-2,2-dimethyl-5,5-bis(propylthio)-1,3,4-oxadiazole in refluxing benzene and in the absence of any electrophile, the resultant bis(propylthio)carbene will dimerize (eq 6).1 Since the reaction is highly exothermic, care must be taken in the execution of this reaction. Use of an explosion shield and slow addition of the carbene precursor are recommended.

Related Reagents.

dimethoxy carbene, cyclohexyl isocyanide.


1. Rigby, J. H.; Laurent, S., J. Org. Chem. 1999, 64, 1766.
2. Rigby, J. H.; Laurent, S.; Dong, W.; Danca, M. D., Tetrahedron 2000, 56, 10101.
3. Rigby, J. H.; Dong, W., Org. Lett. 2000, 2, 1673.
4. Rigby, J. H.; Deur, C.; Heeg, M. J., Tetrahedron Lett. 1999, 40, 6887.
5. (a) Rigby, J. H.; Qabar, M., J. Am. Chem. Soc. 1991, 113, 8975. (b) Rigby, JH.; Qabar, M.; Ahmed, G.; Hughes, R. C., Tetrahedron 1993, 49, 10219.
6. Rigby, J. H.; Cavezza, A.; Heeg, M. J., J. Am. Chem. Soc. 1998, 120, 3664.
7. Rigby, J. H.; Danca, M. D., Tetrahedron Lett. 1999, 40, 6891.
8. (a) Hoffmann, R. W.; Steinbach, K.; Dittrich, B., Chem. Ber. 1973, 106, 2174. (b) Lemal, D. M.; Gosselink, E. P.; McGregor, S. D., J. Am. Chem. Soc. 1966, 88, 582. (c) El-Saidi, M.; Kassam, K.; Pole, DL.; Tadey, T.; Warkentin, J., J. Am. Chem. Soc. 1992, 114, 8751. (d) Hoffmann, RW.; Reiffen, M., Chem. Ber. 1976, 109, 2565.

Nancy A. Neale

Wayne State University, Detroit, MI, USA



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