[39085-59-1]  · C15H26N2O2S  · 2,4,6-Triisopropylbenzenesulfonylhydrazide  · (MW 298.50)

(used as a diazene equivalent;3 condensed with ketones and aldehydes to form hydrazones that can be converted into reactive intermediates such as diazoalkanes, carbenes,13 carbenium ions, alkyllithiums,9 or umpolung synthons)

Alternate Name: trisyl hydrazide; TPSH.

Physical Data: mp 121-122 °C (dec).

Solubility: sol virtually all ethereal, halogenated, protic, and aprotic solvents; insol water and hydrocarbon solvents.

Analysis of Reagent Purity: NMR, IR, TLC.

Preparative Methods: may be prepared in 96% yield by treating commercially available 2,4,6-triisopropylbenzenesulfonyl chloride2 with hydrazine hydrate in THF,3,4 being careful to keep the reaction and workup temperatures below or around 0 °C. The solid can be dried in vacuo over P2O5 for 24 h.

Handling, Storage, and Precautions: decomposes rapidly in solution at rt to diazene, particularly under basic or neutral conditions; acid retards this degradation significantly. It is stable in solid form at -20 °C for months and may be freed from acidic impurities as described in the literature.3 2,4,6-Triisopropylbenzenesulfonylhydrazide is a toxic, potentially flammable solid which should be handled with gloves under an inert atmosphere.

Alkene Reduction.

2,4,6-Triisopropylbenzenesulfonyl hydrazide (TPSH) undergoes solvent-dependent thermal degradation into diazene (diimide) between 35 and 65 °C, resulting in the in situ reduction of alkenes and other double bonds in good to excellent yields.3-6 TPSH remains one of the best sources of diazene, and addition of amine bases increases the rate of both diazene formation and hydrogenation. It is the most reactive of the common arenesulfonylhydrazides, being 380 and 24 times more reactive than p-Toluenesulfonylhydrazide and Mesitylenesulfonylhydrazide, respectively, under base-catalyzed conditions.3

Formation of Hydrazones.

Much of the rich chemistry exhibited by TPSH comes from its condensation products with ketones and aldehydes. Such trisyl hydrazones are typically prepared in excellent yield by mixing equimolar amounts of reagents in methanol or ethanol at room temperature with a catalytic amount of acid such as HCl and storing the reaction in the cold.7 The product precipitates and is filtered off. Very hindered ketones such as camphor and diisopropyl ketone require stoichiometric amounts of acid and extraordinarily hindered ketones may not condense at all.1,8

Electrophilic Additions to Hydrazone Anions.

Trisylhydrazones can be quantitatively deprotonated with 2 equiv of n-Butyllithium to give dianions which are highly nucleophilic and participate in alkylation, aldol, halogenation, and epoxide-opening reactions at low temperature.9 Regioselectivity of deprotonation is dictated by three factors. First, and most important, is the geometry of the hydrazone C=N double bond, since the second equivalent of base is directed syn to the sulfonamide nitrogen anion in ethereal solvents.10 Thus the mixture of azaenolates is determined by the ratio of isomeric hydrazones. TMEDA solvent negates the syn-directing effect and has been used extensively to deprotonate the less substituted a-carbon independent of hydrazone geometry.11 Second, anion-stabilizing substituents in the a-position direct deprotonation. Third, is a general rule that methyl > methylene > methine in acidity. The preferred proton abstracted is illustrated with arrows in eq 1.9d,12

Bamford-Stevens and Shapiro Reactions.

Thermal decomposition of the monoanions of arenesulfonylhydrazones in aprotic solvents such as glyme (the aprotic Bamford-Stevens reaction13) is a method of choice for forming diazo compounds and carbenes. Trisylhydrazones are well suited to this end and have been shown to be the superior reagent for diazoalkane formation in several instances (eq 2).14

Trisylhydrazones were originally investigated as an alternative to the shortcomings of tosylhydrazones in the Shapiro reaction.12a The former have the advantage that their anions decompose at lower temperatures and the bulky isopropyl substituents preclude ortho metalation, enabling the use of stoichiometric amounts of base. Acyclic azaenolates have a strong preference for (E)CC geometry10 and undergo the Shapiro elimination to stereoselectively produce alkenes of (Z) geometry (eqs 3 and 4). The stereochemical fidelity of the azaenolate is compromised significantly, however, if there is hydrocarbon branching at the a-center due to allylic strain.1

The resulting vinyllithium intermediates may be trapped with a proton or some of the representative electrophiles shown in eqs 3-6.11,15

Additional electrophiles include CO2, DMF, formaldehyde, ethyl chloroformate, ketones, D2O, halophosphines, halides, and propargylic tosylates.9d,11,12a,16

The Shapiro elimination also provides access to a diverse array of one-pot electrophile-substituted double bonds (eqs 7 and 8).9

Several investigators have attenuated the potent nucleophilicity of vinyllithium intermediates by transmetalation or trapping. Vinylstannanes,17 chromium-carbene complexes,18 and particularly vinylsilanes19,20 have been prepared. Alkenyllithiums react faithfully to give 1,2-addition products with a,b-unsaturated ketones, and mixed cuprate reagents have also been prepared with some success by trapping vinyllithiums with phenylthiocopper for 1,4-addition (eq 9).21,22

Intercepting the vinyllithium with a trialkylboron Lewis acid (eq 10) forms an ate complex that can then undergo iodine-promoted alkyl migration and elimination to give excellent yields of hindered trisubstituted alkenes.23,24 This transformation constitutes a formal SN2 displacement of a secondary halide and appears generally applicable to cyclic and acyclic ketones.

Intramolecular vinyllithium trapping has been used as an alternative to radical cyclization. Five- to seven-membered ring alkylidene cycloalkanes are formed via SN2 displacement of a hydrocarbon-tethered leaving group by an alkenyllithium intermediate in 30-72% yield.25 Another more general alternative is an analogous alkenyllithium condensation with a tether containing an unactivated terminal alkene (eqs 11 and 12).26,27

The resulting alkyllithium produced after cyclization has also been successfully trapped with several electrophiles in fair to excellent yield. This annulation stereoselectively gives the syn isomer in 10:1 to >50:1 but is limited to five-membered ring formation and has not been applied to highly functionalized carbocycles.

Condensation of trisylhydrazones with a,b-unsaturated ketones yields hydrazones that are selectively deprotonated a rather than g to form 2-lithioalkadienes or quenched to form dienes (eqs 13 and 14).28 2-Halo ketone hydrazones give the same intermediate after treatment with strong base.29


Ketones may be homologated by one carbon in moderate yield by forming the trisylhydrazone and reacting it with cyanide ion in boiling methanol.30 1,2-Carbonyl transpositions are possible in good to excellent yield by sulfenylation of a trisylhydrazone dianion, Shapiro elimination, and hydrolysis of the thioenol ether.31 Vinylsilanes have been used to the same end.32 Hydrazones of amides (amidrazones) have been prepared indirectly by treatment of a trisyl carbazate with Phosphorus(V) Chloride and then Morpholine. These compounds act as acyl anion equivalents and may also undergo the Shapiro elimination to form a lithio enamine which can be attacked by two electrophiles.33 Finally, trisylhydrazones of a-keto amides may be indirectly synthesized from isocyanides; when treated with alkyllithium base, they undergo the Shapiro reaction to give allenylates. These intermediates react with electrophiles to give a-substituted-a,b-unsaturated amides in good to excellent yield.34

1. Chamberlin, A. R.; Bloom, S. H. OR 1990, 39, 1.
2. Lohrmann, R.; Khorana, H. G. JACS 1966, 88, 829.
3. Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. T 1976, 32, 2157.
4. Cusack, N. J.; Reese, C. B.; Roozpeikar, B. CC 1972, 1132.
5. Garbisch, E. W., Jr.; Schildcrout, S. M.; Patterson, D. B.; Sprecher, C. M. JACS 1965, 87, 2932.
6. For a review of diazene reduction of alkenes, see Hünig, S.; Müller, H. R.; Thier, W. AG(E) 1965, 4, 271.
7. Bertz, S. H.; Dabbagh, G. JOC 1983, 48, 116.
8. Smith, A. B., III; Jerris, P. J. JOC 1982, 47, 1845.
9. (a) Adlington, R. M.; Barrett, A. G. M. JCS(P1) 1981, 2848. (b) Adlington, R. M.; Barrett, A. G. M. CC 1979, 1122. (c) Adlington, R. M.; Barrett, A. G. M. CC 1978, 1071. (d) Bond, F. T.; DiPietro, R. A. JOC 1981, 46, 1315. (e) Engel, P. S.; Culotta, A. M. JACS 1991, 113, 2686.
10. Bergbreiter, D. E.; Newcomb, M. Asymmetric Synthesis; Academic: San Diego, 1983; Vol. 2.
11. Chamberlin, A. R.; Bond, F. T. S 1979, 44.
12. (a) Chamberlin, A. R.; Bond, F. T. JOC 1978, 43, 147. (b) Shapiro, R. H.; Lipton, M. F.; Kolonko, K. J.; Buswell, R. L.; Capuan, L. A. TL 1975, 1811. (c) Traas, P. C.; Boelens, H.; Tokken, H. J. TL 1976, 2287. (d) Jones, F. K.; Denmark, S. E. HCA 1983, 66, 2377.
13. Shapiro, R. H. OR 1976, 23, 405.
14. (a) Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. JOC 1978, 43, 154. (b) Dudman, C. C.; Grice, P.; Reese, C. B. TL 1980, 21, 4645. (c) Dudman, C. C.; Reese, C. B. S 1982, 419. (d) Ok, H.; Caldwell, C.; Schroeder, D. R.; Singh, A. K.; Nakanishi, K. TL 1988, 29, 2275. (e) Jin, F.; Xu, Y.; Ma, Y. TL 1992, 33, 6161. (f) Dirdonan, C. D.; Reese, C. B. S 1982, 419.
15. (a) Chamberlin, A. R.; Liotta, E. L.; Bond, F. T. OS 1983, 61, 141. (b) Engel, P. S.; Culotta, A. M. JACS 1991, 113, 2686. (c) Schore, N. E.; Knudsen, M. J. JOC 1987, 52, 569.
16. (a) Oppolzer, W.; Begley, T.; Ashcroft, A. TL 1984, 25, 825. (b) Wasserman, H. H.; Fukuyama, J. M. TL 1984, 25, 1387. (c) Mislanker, D. G.; Mugrage, B.; Darling, S. D. TL 1981, 22, 4619. (d) Baudouy, R.; Sartoretti, J. T 1983, 39, 3293.
17. Corey, E. J.; Estreicher, H. TL 1980, 21, 1113.
18. Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson, S. R. T 1985, 41, 5813.
19. Daniels, R. G.; Paquette, L. A. OM 1982, 1, 1449.
20. Stevens, K. E.; Paquette, L. A. TL 1981, 22, 4393.
21. Stemke, J. R.; Chamberlin, A. R.; Bond, F. T. TL 1976, 2947.
22. Kende, A. S.; Jungheim, L. N. TL 1980, 21, 3849.
23. Baba, T.; Avasthi, K.; Suzuki, A. BCJ 1983, 56, 1571.
24. Avasthi, K.; Baba, T.; Suzuki, A. TL 1980, 21, 945.
25. Chamberlin, A. R.; Bloom, S. H. TL 1984, 25, 4901.
26. Chamberlin, A. R.; Bloom, S. H. TL 1986, 27, 551.
27. Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H. JACS 1988, 110, 4788.
28. (a) Kozikowski, A. P.; Li, C.-H. JOC 1987, 52, 3541. (b) Brown, P. A.; Jenkins, P. R. JCS(P1) 1986, 1129. (c) Brown, P. A.; Jenkins, P. R. TL 1982, 23, 3733.
29. Paquette, L. A.; Daniels, R. G.; Gleiter, R. OM 1984, 3, 560.
30. Jiricny, J.; Orere, D. M.; Reese, C. B. JCS(P1) 1980, 1487.
31. Mimura, T.; Nakai, T. CL 1980, 931.
32. Fristad, W. E.; Bailey, T. B.; Paquette, L. A. JOC 1978, 43, 1620.
33. Baldwin, J. E.; Bottaro, J. C. CC 1981, 1121.
34. (a) Adlington, R. M.; Barrett, A. G. M.; Quayle, P.; Walker, A. JCS(P1), 1983, 605. (b) Adlington, R. M.; Barrett, A. G. M. CC 1981, 65. (c) Adlington, R. M.; Barrett, A. G. M. T 1981, 37, 3935.

A. Richard Chamberlin & James E. Sheppeck II

University of California, Irvine, CA, USA

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