[1519-39-7]  · C8H9LiOS  · p-Tolylsulfinylmethyllithium  · (MW 160.18)

(asymmetric synthesis; adds diastereoselectively to carbonyl compounds,1 esters,1 imines,1b,f nitrones,2 and nitrile oxides3)

Physical Data: stable in THF even above 0 °C.

Solubility: sol THF.

Form Supplied in: generated in situ from precursors, (R)-(+)-Methyl p-Tolyl Sulfoxide, mp 73-75 °C, [a]20 +145° (c = 2, acetone), and (S)-(-)-methyl p-tolyl sulfoxide, mp 75-77 °C, [a]20 -147° (c = 2, acetone), both of which are commercially available and can also be prepared by a number of methods.1,4

Preparative Method: prepared in situ by the reaction of enantiomers of methyl p-tolyl sulfoxide with Lithium Diethylamide or Lithium Diisopropylamide in THF at 0 to -78 °C.1

Handling, Storage, and Precautions: highly sensitive to air and moisture. Its generation and handling must be carried out under an inert atmosphere of nitrogen or argon. Normally, preparation is carried out immediately prior to use.


Most of the synthetic applications are carried out with (R)-(+)-p-tolylsulfinylmethyllithium. The carbanion undergoes copper-promoted oxidative dimerization to the optically pure 1,2-bis-sulfoxide (eq 1).5

Addition to Carbonyl Compounds.

The addition of p-tolylsulfinylmethyllithium to carbonyl compounds gives the b-hydroxy-a-p-tolylsulfinyl adducts in poor diastereoselectivity; normally, an approximately 1:1 diastereomeric mixture is obtained.6 The diastereoselection with benzaldehyde is improved to about 80% with the addition of Zinc Chloride.7 Although proceeding with a poor diastereoselectivity, the reaction can be applied to the asymmetric synthesis of optically active alcohols. The two diastereomeric adducts can be separated by chromatography. Desulfinylation of each diastereomer gives the corresponding optically active alcohol (eq 2).6 Optically active alcohols can also be prepared from epoxides (eq 3).6

(R)-(+)-trans-b-Styryl p-tolyl sulfoxide, produced by the reaction of the benzaldehyde adduct with excess Sodium Hydride and Iodomethane, undergoes selective Michael reaction with diethyl sodiomalonate to give the (RC,RS) product as the major isomer, which can be obtained in pure form by fractional crystallization. The product can be transformed into optically active (-)-3-phenylbutyric acid (eq 4).8

The dianion of (R)-3-(p-tolylsulfinyl)propionic acid, prepared from the alkylation product of p-tolylsulfinylmethyllithium with lithium bromoacetate, adds to aldehydes to give diastereomeric lactones which can be separated by chromatography; their pyrolyses give optically pure 5-substituted furan-2(5H)-ones (eq 5).9

Addition to Esters.

Racemic p-tolylsulfinylmethyllithium reacts with (R)-(-)-menthyl benzoate in enantiodifferentiating fashion to give the corresponding optically active b-keto sulfoxide together with optically active methyl p-tolyl sulfoxide which has the opposite configuration.10 A similar result is obtained in the reaction of ethyl carboxylates in the presence of (-)-sparteine (eq 6).11 The optically active b-keto sulfoxides, which are very important chiral synthons for the synthesis of optically active materials, are normally prepared by the reaction of (R)-p-tolylsulfinylmethyllithium with carboxylic acid esters.1a p-Tolylsulfinylmethyl phenyl ketone reacts with Diethylaluminum Cyanide in toluene diastereoselectively to give one diastereomer of the corresponding cyanohydrin which can be transformed into the optically active alcohol (eq 7).12

b-Hydroxy sulfoxides of opposite stereochemistry can be prepared in very high diastereomeric excesses (90-95%) by the reduction of b-keto sulfoxides with Lithium Aluminum Hydride, Diisobutylaluminum Hydride, or DIBAL/ZnCl2.13 The optically pure diastereomers of the b-hydroxy sulfoxides can be transformed into optically active epoxides (eq 8),14 alcohols (eq 9),15 and 4-substituted butenolides (eq 10).16

Addition to Arenesulfinic Esters.

The reaction of (R)-(+)-p-tolylsulfinylmethyllithium with (-)-menthyl (S)-p-toluenesulfinate gives (S,S)-bis(p-tolylsulfinyl)methane. (S)-(-)-p-Tolylsulfinylmethyllithium reacts similarly with (-)-menthyl (S)-p-toluenesulfinate, producing (R,S)-bis(p-tolylsulfinyl)methane (eq 11).4c In contrast to the poor diastereoselection in the reaction of (R)-(+)-p-tolylsulfinylmethyllithium with carbonyl compounds, (S,S)-(+)-bis(p-tolylsulfinyl)methyllithium reacts with aromatic aldehydes with high diastereoselectivity. Its reaction with a,b-unsaturated aldehydes yields 4-substituted (E,E)-(S,S)-1,1-bis(p-tolylsulfinyl)-1,3-butadiene (eq 12).17

Addition to Imines.

The addition of (R)-(+)-p-tolylsulfinylmethyllithium to benzylideneaniline produces (RSRS)-(+)-N-phenyl-2-amino-2-phenylethyl p-tolyl sulfoxide in high diastereoselectivity (eq 13).18 Acyclic and cyclic imines react similarly. The chair transition state can account for the diastereoselective process. Detailed investigations reveal that diastereoselectivity depends on several factors, i.e. the temperature used for deprotonation of methyl p-tolyl sulfoxide (optimum conditions: LDA, THF, 0 °C)18c and kinetically and thermodynamically controlled reaction conditions. Equilibrium between the diastereomeric adducts is thought to occur over the timescale of the addition reaction. Diastereoselectivity is better under kinetic control than under the thermodynamic control.18b This methodology has been applied to the syntheses of (R)-(+)-carnegine and (R)-(+)-tetrahydropalmatine (eq 14).19

(R)-(+)-p-Tolylsulfinylmethylmagnesium bromide reacts with 4-bromobutanenitrile to provide (R)-(+)-4,5-dihydro-2-(p-tolylsulfinylmethyl)-3H-pyrrole in low yield (eq 15).20 This pyrrole derivative, which can be prepared in 92% yield by reaction of a-lithiated 3,4-dihydro-5-methyl-2H-pyrrole with (S)-(-)-menthyl p-toluenesulfinate, is utilized in the syntheses of (+)-elaeokanine A and (-)-elaeokanine B (eq 16).20b A similar approach has been utilized in the synthesis of yohimban alkaloids (eq 17).20c

Addition to Nitrones and Nitrile Oxides.

The reaction with 6,7-dimethoxy-3,4-dihydroisoquinoline N-oxide in the presence of quinidine is a highly diastereoselective process. The N-hydroxytetrahydroisoquinoline adduct can be desulfurized to (R)-(+)-salsolidine (eq 18).2b The addition of (R)-(+)-p-tolylsulfinylmethyllithium to arylnitrile oxides gives b-oximino sulfoxides with high optical purity (eq 19).3

Related Reagents.

Methyl Phenyl Sulfone; Phenylthiomethyllithium.

1. (a) Solladié, G. S 1981, 185. (b) Walker, A. J. TA 1992, 3, 961. (c) Durst, T. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 3, Chapter 11.6. (d) Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1983; Vol. 2. (e) Burbachyn, M. R.; Johnson, C. R. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984; Vol. 3, Chapter 2. (f) Ogura, K. COS 1991, 1, Chapter 2.3. (g) Krief, A. COS 1991, 3, Chapter 1.3.
2. (a) Pyne, S. G.; Hajipour, A. R. T 1992, 48, 9385. (b) Murahashi, S.-I.; Sun, J.; Tsuda, T. TL 1993, 34, 2645.
3. Annunziata, R.; Cinquini, M. S 1982, 929.
4. (a) Andersen, K. K. TL 1962, 93. (b) Mislow, K.; Green, M. M.; Laur, P.; Melillo, J. T.; Simmons, T.; Ternay, A. L., Jr. JACS 1965, 87, 1958. (c) Kunieda, N.; Nokami, J.; Kinoshita, M. BCJ 1976, 49, 256. (d) Solladié, G.; Hutt, J.; Girardin, A. S 1987, 173.
5. Maryanoff, C. A.; Maryanoff, B. E.; Tang, R.; Mislow, K. JACS 1973, 95, 5839.
6. (a) Tsuchihashi, G.-I.; Iriuchijima, S.; Ishibashi, M. TL 1972, 4605. (b) Kunieda, N.; Kinoshita, M.; Nokami, J. CL 1977, 289.
7. Braun, M.; Hild, W. CB 1984, 117, 413.
8. (a) Tsuchihashi, G.-I.; Mitamura, S.; Inoue, S.; Ogura, K. TL 1973, 323. (b) Iwasaki, F.; Mitamura, S.; Tsuchihashi, G.-I. BCJ 1978, 51, 2530.
9. Albinati, A.; Bravo, P.; Ganazzoli, F.; Resnati, G.; Viani, F. JCS(P1) 1986, 1405.
10. Kunieda, N.; Suzuki, A.; Kinoshita, M. BCJ 1981, 54, 1143.
11. Kunieda, N.; Kinoshita, M. PS 1981, 10, 383.
12. Ruano, J. L. G.; Castro, A. M. M.; Rodriguez, J. H. TL 1991, 32, 3195.
13. (a) Solladié, G.; Greck, C.; Demailly, G.; Solladié-Cavallo, A. TL 1982, 23, 5047. (b) Carreño, M. C.; Ruano, J. L. G.; Martín, A. M.; Pedregal, C.; Rodriguez, J. H.; Rubio, A.; Sanchez, J.; Solladié, G. JOC 1990, 55, 2120.
14. Solladié, G.; Demailly, G.; Greck, C. TL 1985, 26, 435.
15. (a) Solladié, G.; Demailly, G.; Greck, C. JOC 1985, 50, 1552. (b) Bravo, P.; Frigerio, M.; Resnati, G. JOC 1990, 55, 4216. (c) Solladie, G.; Fernandez, I.; Maestro, C. TL 1991, 32, 509.
16. Solladié, G.; Fréchou, C.; Demailly, G.; Greck, C. JOC 1986, 51, 1912.
17. Solladié, G.; Colobert, F.; Ruiz, P.; Hamdouchi, C.; Carreño, M. C.; Ruano, J. L. G. TL 1991, 32, 3695.
18. (a) Tsuchihashi, G.-I.; Iriuchijima, S.; Maniwa, K. TL 1973, 3389. (b) Pyne, S. G.; Dikic, B. CC 1989, 826. (c) Ronan, B.; Marchalin, S.; Samuel, O.; Kagan, H. B. TL 1988, 47, 6101.
19. (a) Pyne, S. G.; Chapman, S. L. CC 1986, 1688. (b) Pyne, S. G.; Dikic, B. JOC 1990, 55, 1932.
20. (a) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto, A.; Panangadan, J. A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding, A. M. JOC 1989, 54, 5659. (b) Hua, D. H.; Bharathi, S. N.; Robinson, P. D.; Tsujimoto, A. JOC 1990, 55, 2128. (c) Hua, D. H.; Bharathi, S. N.; Panangadan, J. A. K.; Tsujimoto, A. JOC 1991, 56, 6998.

Vichai Reutrakul & Manat Pohmakotr

Mahidol University, Bangkok, Thailand

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