2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-Disulfide1

[19172-47-5]  · C14H14O2P2S4  · 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-Disulfide  · (MW 404.45)

(reagent for the conversion of carbonyl into thiocarbonyl groups1)

Alternate Name: Lawesson's reagent.

Physical Data: mp 228-229 °C.

Solubility: modestly sol boiling organic solvents such as toluene, chlorobenzene, anisole, dimethoxyethane.

Form Supplied in: yellowish evil-smelling crystals; typical impurity is P4S10.

Analysis of Reagent Purity: FTIR spectrum.1c

Preparative Methods: reaction of P4S10 with anisole in excess refluxing anisole.2

Purification: recrystallization from boiling toluene.

Handling, Storage, and Precautions: can be stored for months at rt if moisture is excluded. Prolonged heating in solution causes decomposition (polymerization). It is toxic and should be handled under a fume hood since hazardous H2S is easily liberated with moisture.

Thionation of Carbonyl Compounds.

Lawesson's reagent (LR) is a most powerful reagent for the thionation of a wide variety of carbonyl compounds. Ketones, enones, carboxylic esters, thiolocarboxylic esters, amides, and related substrates are conveniently transformed into the corresponding thiocarbonyl compounds.1 In some cases, follow-up products are isolated since certain thiones are labile under the reaction conditions. Compared with P4S10, from which it is easily prepared,2 LR exhibits several advantages. Its reactivity is significantly higher and it is sufficiently soluble in hot organic solvents, allowing homogeneous reaction conditions to be applied. Therefore many carbonyl compounds can be successfully thionated with LR but not with P4S10, or at least thionated in higher yields. Several reagents with structures similar to LR, which are even more reactive or more selective than LR, have been developed and are used in particularly difficult cases (see 2,4-Bis(methylthio)-1,3,2,4-dithiadiphosphetane 2,4-Disulfide). The workup procedure depends on the reaction conditions applied, in particular on the solvent, and the products formed. If DME is used, the reaction mixture can be poured into water and the product extracted as usual. Low boiling hydrocarbons are best evaporated and the residue, which contains the product together with 2,4,6-tris(4-methoxyphenyl)cyclotriphosphoxane 2,4,6-trisulfide, is subjected to column chromatography. High boiling solvents such as tetralin or trichlorobenzene should be removed by flash chromatography in order to avoid thermal decomposition of the labile thiones.


Thioketones of different types have been obtained from the corresponding ketones. Lawesson, who discovered LR to be a powerful reagent for the conversion of C=O into C=S groups, described the preparation of diaryl thioketones.3 Substituents such as Me, Br, NO2, or NMe2 do not affect the good yields of up to 98% (eq 1).

Recently, the diferrocenyl thioketones (1) and (2) were prepared from the corresponding ketones.4 Alkyl aryl and dialkyl thioketones (3),3 (4),5 (5)6 are formed in good yields if enethiolization is unfavored or impossible, whereas mainly enethiols are obtained from cycloalkanones (eq 2).7

2-Cyclohexenones are thionated with LR (eq 3),7 but only the vinylogous dithioester (6) is a stable compound. Acyclic enones (chalcones) give on reaction with LR the enethione dimers (eq 4).8

Again, stable enethiones are formed if an electron donating substituent (e.g. NR2) is present in the b-position (eq 5).9 Certain isolable 2,5-cyclohexadienethiones can be further transformed into bicyclohexadienylidenes (eq 6).10

The thioanalogs of natural products such as the steroid (7)11 or the colchicine alkaloid (8)12 have also been prepared by use of LR.

Thio Analogs of Dicarbonyl Compounds.

In general, the most labile thiono analogs of a-dicarbonyl compounds cannot be prepared by any thionation procedure. However, thioacenaphthoquinone (9) as well as thioanthraquinone (10) were obtained from the quinones and LR.13 Even a-thioxo thioamides are available (eq 7),14 whereas 2,2,5,5-tetramethyl-4-thioxo-3-hexanone, which itself cannot be prepared from the corresponding diketone, reacts with LR to yield 3,4-di-t-butyl-1,2-dithiete, the valence isomer of the open-chain dithione (eq 8).15

Thioketones with pronounced steric hindrance are obtained on reaction of cyclobutane-1,3-diones with LR (eq 9).16

Diketones with remote C=O groups can be transformed by LR into the mono- or dithiones.17

Thiono Esters and Lactones.

Although thiono esters can be conveniently prepared via imidates,18 the introduction of LR for the thionation of esters3 represents a great advance in synthetic methodology since ordinary esters are used as educts and P4S10 only reacts with esters if enforced reaction conditions are applied, under which many thiono esters decompose. Facile conversion of aliphatic and aromatic esters (eq 10),3,19 a,b-unsaturated esters,20 and lactones21 to the corresponding thiono derivatives is effected in high yields (eqs 11 and 12).22,23

Thiono esters and lactones are important intermediates in modern organic synthesis since they easily undergo useful follow-up reactions. Ethers are formed on reduction with Raney Nickel24 or Tri-n-butylstannane (eq 13).25

Macrocyclic bis-thionolactones have been prepared with LR. These were converted by reduction with Sodium Naphthalenide into the radical anions, which gave bicyclic systems through radical dimerization and subsequent methylation (eq 14).26 This method was successfully applied by Nicolaou et al.27 in the total synthesis of hemibrevetoxin B. One of the crucial steps of the synthesis was the preparation of the bis-thiono ester (11), which was achieved by using LR together with tetramethylthiourea in xylene at 175 °C.27

Dithioesters and Related Compounds.

Thioesters are transformed into the corresponding dithioesters on reaction with LR.3,20,28 Again the yields are nearly quantitative even if steric hindrance can be expected (eq 15).3

The reaction is completed within 5-15 min if tetralin at 210 °C is used as solvent.28 Also, dithio-g-lactones,21,28 including dithiophthalides29 and dithio-a-pyrones,30 are formed smoothly whereas the hitherto unknown simple b- or d-dithiolactones cannot be prepared, neither with LR nor by any other method. Interestingly, dithiopilocarpine is formed as a mixture of diastereomers on reaction of pilocarpine with LR (eq 16), i.e. both oxygen atoms of (12) are replaced by sulfur.31 In an interesting sequence of thionation and rearrangement reactions, three different thiono analogs of 1,8-naphthalic anhydride were prepared (eq 17).32

Thioamides and Related Compounds.

Thioamides are the most stable thiocarbonyl compounds and have been prepared, for a century, from amides and P4S10 under rather drastic conditions. However, even for this purpose LR has turned out to be a superior reagent. High yields are obtained for all types of thioamides1,33 and -lactams1,33,34 including the elusive unsubstituted acrylothioamide (eq 18)35 and thioformamides or thioamides bearing sensitive substituents such as NO2, Z-NH,36 or OH (eq 19).33

b-Lactams are also smoothly transformed34 (eq 20),37 which is important for the preparation of thio analogs of b-lactam antibiotics or azetidines. Furthermore, endothio oligopeptides became conveniently available only after LR had been introduced as reagent1,38,39 (eq 21).40

Recently the cyclopeptide [D-cysteine]8cyclosporin has been prepared from [D-serine]8cyclosporin via selective thionation with LR at the 7-position followed by intramolecular sulfur transfer.41

Miscellaneous Reactions of LR.

Under particular conditions, certain carbonyl compounds and other substrates react with LR to form thiophosphonates or heterocycles, which fact throws some light on the mechanism of thionation reactions with LR.1 Carbinols undergo nucleophilic substitution with LR to form the corresponding thiols.42 The redox properties of LR can be utilized to prepare dithiolactones from dialdehydes (eq 22),43 a-oxo thioamides from nitro ketones (eq 23),44 or sulfides from sulfoxides.45

1. (a) Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N. T 1985, 41, 2567. (b) Cava, M. P.; Levinson, M. I. T 1985, 41, 5061. (c) Aldrich Library of Infrared Spectra; Aldrich Chemical Co.: Milwaukee, 1985; Vol. 1 (2), p 557B.
2. Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. OS 1984, 62, 158.
3. Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. BSB 1978, 87, 223.
4. Sato, M.; Asai, M. JOM 1992, 430, 105.
5. Klages, C.-P.; Voss, J. CB 1980, 113, 2255.
6. Wenck, H.; de Meijere, A.; Gerson, F.; Gleiter, R. AG(E) 1986, 25, 335.
7. Scheibye, S.; Shabana, R.; Lawesson, S.-O.; Rømming, C. T 1982, 38, 993.
8. Kametani, S.; Ohmura, H.; Tanaka, H.; Motoki, S. CL 1982, 793.
9. (a) Walter, W.; Proll, T. S 1979, 941. (b) Shabana, R.; Rasmussen, J. B.; Olesen, S. O.; Lawesson, S.-O. T 1980, 36, 3047. (c) Rasmussen, J. B.; Shabana, R.; Lawesson, S.-O. T 1982, 38, 1705. (d) Pulst, M.; Greif, D.; Kleinpeter, E. ZC 1988, 28, 345.
10. Kühn, R.; Otto, H.-H. AP 1989, 322, 375.
11. Weiss, D.; Gaudig, U.; Beckert, R. S 1992, 751.
12. Muzaffar, A.; Brossi, A. SC 1990, 20, 713.
13. El-Kateb, A. A.; Hennawy, I. T.; Shabana, R.; Osman, F. H. PS 1984, 20, 329.
14. Adiwidjaja, G.; Günther, H.; Voss, J. LA 1983, 1116.
15. Köpke, B.; Voss, J. JCR(S) 1982, 314.
16. Strehlow, T.; Voss, J.; Spohnholz, R.; Adiwidjaja, G. CB 1991, 124, 1397.
17. Ishii, A.; Nakayama, J.; Ding, M.; Kotaka, N.; Hoshino, M. JOC 1990, 55, 2421.
18. Voss, J. COS 1991, 6, 435.
19. Jones, B. A.; Bradshaw, J. S. CRV 1984, 84, 17.
20. Pedersen, B. S.; Scheibye, S.; Clausen, K.; Lawesson, S.-O. BSB 1978, 87, 293.
21. Scheibye, S.; Kristensen, J.; Lawesson, S.-O. T 1979, 35, 1339.
22. Takano, S.; Tomita, S.; Takahashi, M.; Ogasawara, K. S 1987, 1116.
23. Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie, W. W.; Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.; Hark, R. R. JACS 1990, 112, 6263.
24. Baxter, S. L.; Bradshaw, J. S. JOC 1981, 46, 831.
25. Smith, C.; Tunstad, L. M.; Guttierrez, C. G. PS 1988, 37, 257.
26. Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.; Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. JACS 1990, 112, 3040.
27. Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, Xiao-Yi; Hwang, C.-K. JACS 1993, 115, 3558.
28. Ghattas, A.-B. A. G.; El-Khrisy, E.-E. A. M.; Lawesson, S.-O. Sulfur Lett. 1982, 1, 69.
29. Oparin, D. A.; Kuznetsova, A. S. Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk 1990, (6), 109 (CA 1991, 115, 29 039y).
30. Hoederath, W.; Hartke, K. AP 1984, 317, 938.
31. Shapiro, G.; Floersheim, P.; Boelsterli, J.; Amstutz, R.; Bolliger, G.; Gammenthaler, H.; Gmelin, G.; Supavilai, P.; Walkinshaw, M. JMC 1992, 35, 15.
32. Lakshmikantham, M. V.; Chen, W.; Cava, M. P. JOC 1989, 54, 4746.
33. Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. BSB 1978, 87, 229.
34. Shabana, R.; Scheibye, S.; Clausen, K.; Olesen, S. O.; Lawesson, S.-O. NJC 1980, 4, 47.
35. Khalid, M.; Vallée, Y.; Ripoll, J.-L. CI(L) 1988, 123.
36. Kohrt, A.; Hartke, K. LA 1992, 595.
37. Verkoyen, C.; Rademacher, P. CB 1985, 118, 653.
38. Thorsen, M.; Yde, B.; Pedersen, U.; Clausen, K.; Lawesson, S.-O. T 1983, 39, 3429.
39. Sherman, D. B.; Spatola, A. F. JACS 1990, 112, 433.
40. Brown, D. W.; Campbell, M. M.; Chambers, M. S.; Walker, C. V. TL 1987, 28, 2171.
41. Eberle, M. K.; Nuninger, F. JOC 1993, 58, 673.
42. Nishio, T. CC 1989, 205.
43. Nugara, P. N.; Huang, N.-Z.; Lakshmikantham, M. V.; Cava, M. P. HC 1991, 32, 1559.
44. Harris, P. A.; Jackson, A.; Joule, J. A. Sulfur Lett. 1989, 10, 117.
45. Bartsch, H.; Erker, T. TL 1992, 33, 199.

Jürgen Voss

Universität Hamburg, Germany

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