p-Toluenesulfonylhydrazide1

[1576-35-8]  · C7H10N2O2S  · p-Toluenesulfonylhydrazide  · (MW 186.26)

(used as a source of diazene;2 condensed with ketones and aldehydes to form hydrazones that can be converted into reactive intermediates such as diazoalkanes, carbenes, carbenium ions, alkyllithiums, or umpolung synthons;7 used in 1,3-dipolar cycloaddition reactions to form N-heterocycles; used to make propargyl aldehydes and ketones via the Eschenmoser fragmentation;44 ketone hydrazones are deoxygenated with mild reagents in a modified Wolff-Kishner reduction50)

Alternate Name: tosyl hydrazide.

Physical Data: mp 108-110 °C (dec).

Solubility: sol virtually all organic solvents except hydrocarbons; insol water.

Form Supplied in: solid; widely available.

Handling, Storage, and Precautions: is thermally labile at elevated temperatures, but can be stored at or below room temperature. It is a toxic, potentially flammable solid which should be handled with gloves under inert atmosphere.

Alkene Reduction/Allylic Diazene Rearrangement.

p-Toluenesulfonylhydrazide may be thermolyzed in solution to generate diazene (diimide) for alkene reduction.2 It is the least reactive member of the common arenesulfonylhydrazides, with Mesitylenesulfonylhydrazide being 24 times more reactive and 2,4,6-Triisopropylbenzenesulfonylhydrazide being 380 times more reactive under base-catalyzed decomposition conditions. The latter has largely supplanted tosyl hydrazide as a source of diazene because of the low-temperature convenience.3,4

Sigmatropic rearrangement of allylic and propargylic diazene intermediates is well established and is a reliable means of alkene synthesis.5 Several options are available to generate these intermediates, such as hydride reduction of tosylhydrazones (refer to eqs 14 and 15), elimination of p-toluenesulfinic acid from an allylic hydrazine (eqs 1 and 2), Wolff-Kishner reduction of an a,b-unsaturated ketone, or oxidation of alkylhydrazines.5

p-Tolyl sulfones have been prepared in excellent yield by halide displacement with toluenesulfinate ion.6

Nucleophilic Addition to Hydrazones.

The bulk of tosyl hydrazide's synthetic utility comes from its condensation products with ketones and aldehydes.7,8 Synthetically useful addition reactions typically only succeed with nonenolizable ketone hydrazones.9,10 The treatment of enolizable ketone tosyl hydrazones with alkyllithium nucleophiles invariably results in the formation of a dianion rather than addition to the azomethine bond. In contrast, aldehyde tosylhydrazones do not form dianions but instead undergo addition with both alkyllithiums and cuprate reagents to give reductive alkylation products.11,12 A versatile extension of this methodology involves either vinyllithium addition to N-t-butyldimethylsilyl tosylhydrazones or the complementary 1,2-addition of alkyllithium to a,b-unsaturated N-t-butyldimethylsilyl tosylhydrazones. Reductive addition in either case produces an N-TBDMS allylic diazene intermediate which undergoes protodesilylation and subsequent 1,5-sigmatropic rearrangement. (E)-Alkenes are prepared with high stereoselectivity due to A1,3-strain in the transition state (eqs 1 and 2), and epimerization of adjacent stereocenters is not observed.5

Other nucleophiles, such as cyanide ion, similarly add to aldehyde and ketone tosylhydrazones, which constitutes a useful one-carbon homologation.13 Diphenylphosphine Oxide or dimethyl phosphite addition followed by decomposition of the intermediate with base or Sodium Borohydride gives alkyldiphenylphosphine oxides and s-alkanephosphonates, respectively.14

Formation of tosylhydrazones from a-halo ketones, followed by vinylogous halide elimination using mild base, gives p-toluenesulfonylazoalkenes, which undergo SN2-type addition of strong nucleophiles (eq 3).15 This sequence constitutes a synthetically useful carbonyl umpolung synthon for introducing nucleophiles in the a-position of ketones. Examples of simple alkyllithium and 1,3-diketone enolate nucleophilic addition are also known.16

In another example, thermolysis of the tosylhydrazone of an a-hydroxy steroid in ethylene glycol without base resulted in reductive dehydroxylation, presumably through rearrangement of an intermediate epoxydiazene.17

Electrophilic Addition to Hydrazone Anions.

a-Deprotonation of tosylhydrazones with 2 equiv of strong base give highly nucleophilic azaenolates that react with a variety of electrophiles.18 Trisyl hydrazones have also received considerable attention for this transformation19 (see 2,4,6-Triisopropylbenzenesulfonylhydrazide. However, some cyclohexanones, such as 4-t-butylcyclohexanone, require tosyl hydrazones for successful alkylation since the corresponding trisyl hydrazones undergo significant Shapiro elimination (see below) even at -78 °C.18c

The regioselectivity of deprotonation for unsymmetrical tosylhydrazones often is high, and is dictated by three factors. In many cases the configuration of the C=N double bond plays an important role since the sulfonamide anion induces syn deprotonation in ethereal solvents.20 Thus the ratio of a vs. a anions reflects the C=N isomeric ratio, which is typically 85:15 (E):(Z) or greater in unsymmetrical ketones.21,22 The syn-directing effect is inoperative in TMEDA solvent, allowing excellent regioselectivity of deprotonation, independent of the hydrazone geometrical isomer population.23 Electron-stabilizing groups in the a-position direct deprotonation, and finally, the acidity of a-hydrogens follows the generalization that methyl > methylene > methine with only a few exceptions.

Bamford-Stevens and Shapiro Reactions.

Tosylhydrazones may be converted into a variety of reactive intermediates depending upon the specific reaction conditions employed. The protic Bamford-Stevens reaction conditions (ethylene glycol; NaOR; heat) give diazoalkane intermediates that, on occasion, can be isolated but more often undergo in situ protonation followed by loss of dinitrogen to give cationic intermediates. These intermediates tend to give the more substituted double bond, but predicting regioselectivity is dubious, and cationic rearrangements are common (eq 4).24

Triisopropylbenzenesulfonyl and mesitylenesulfonyl hydrazones are far superior to tosyl hydrazones if isolation of the diazo compound is desired, primarily because much lower temperatures are required to induce the sulfinate elimination.25

The aprotic Bamford-Stevens reaction involves deprotonation of the acidic sulfonamide hydrogen in an aprotic solvent (e.g. glyme) to form a salt (Li, Na, and K are common) which is pyrolyzed or photolyzed to generate carbenes (eq 5).26

Five- and six-membered ring ketones usually undergo 1,2-hydride migration to preferentially give the more substituted alkene.27,12,4 Regioselectivity is usually modest but high selectivity is found in some instances, such as the synthesis of furanose glycals,28 D2 unsaturation in trans-A/B steroids, and D3 unsaturation in cis-A/B steroids.29 Nevertheless, examples of competitive cyclopropanation30 and C-H bond insertion in medium-sized rings31 abound.

The Shapiro reaction is extremely useful for the regioselective conversion of ketones into alkenes.1 The anions of tosylhydrazones eliminate p-toluenesulfinate and dinitrogen between 0 °C and room temperature over the course of several hours to give the corresponding least-substituted alkene. Acyclic azaenolates have a strong preference for ECC geometry and react equally well to yield (Z)-alkenes stereoselectively unless a-branching causes too much allylic strain in the transition state.1a,3,8,32 This method has been used extensively in the synthesis of natural products such as alkaloids,33 prostaglandins,34 and especially terpenes (eq 6).24a,35

The intermediate in this reaction is an alkenyllithium, which can be trapped under certain conditions with electrophiles,21,36 providing general access to allylic alcohols, a,b-unsaturated aldehydes and acids,37 vinyl halides, vinyl sulfides,38 and vinylsilanes.39 Use of trisylhydrazones typically gives superior results because the intermediate alkenyllithium is formed at lower temperature and does not require excess base to circumvent quenching of the intermediate by orthometalation.40,21 Tandem one-pot electrophilic addition/Shapiro elimination sequences reliably provide alkenes with highly variable substitution patterns (eq 7), including tetrasubstitution.18c

Tosylhydrazones of a,b-unsaturated ketones likewise participate in the Shapiro elimination to give 2-lithioalkadiene intermediates which may be protonated to give the corresponding dienes, or be trapped with electrophiles.41 Regioselectivity cannot be predicted with certainty, but in general an a-proton is removed (giving the cross-conjugated azaenolate) in preference to a g-proton, once again analogous to the kinetic deprotonation of a,b-unsaturated ketones.42 Tosylhydrazones of b-keto esters are deprotonated to give trianions that decompose to give b,g-unsaturated esters in fair yield.22,8 Cyclic 1,3-diketone monotosylhydrazones analogously give enones when treated with Potassium Carbonate.43

Eschenmoser Fragmentation and Related Eliminations.

Preparation of macrocyclic cycloalkynones by fragmentation of a,b-epoxy ketones is also possible with this reagent (eq 8).44

These fragmentation reaction conditions are too harsh to give the corresponding propargylic aldehydes in good yield.45 More recently, other reagents have proved more efficacious for this transformation (see 2,4-Dinitrobenzenesulfonylhydrazide and Mesitylenesulfonylhydrazide).

Arenesulfonylhydrazones with leaving groups in the a-position proceed through well-documented intermediates or related fragmentation reactions. For instance, treatment of a-bromotosylhydrazones with mild base triggers vinylogous halide elimination to give tosylazoalkenes (eq 9, and also refer to eq 3 and related text). Addition of strong base to these compounds provides 2-lithioalkadienes46 and is a complementary route to the enone method described above.

In acyclic cases the same intermediates seem to eliminate differently to give alkynes (eq 10).47 Eq 11 illustrates a Shapiro elimination in which the resultant vinyllithium intermediate fragments by displacing alkoxide to give the unanticipated hydroxyalkyne in high yield.48 If deprotonation occurs on the a-carbon not occupied by the leaving group, the alkenyllithium intermediate fragments to a hydroxyallene in fair yield (eq 12).49

Reductions of Tosylhydrazones.50

Reduction of aldehyde and ketone tosylhydrazones in a Wolff-Kishner-type reaction was first described using Lithium Aluminum Hydride which was effective in several cases, but proved to be basic enough to produce Shapiro elimination side products.51,52 More recently, milder reductions such as Sodium Borohydride, Sodium Trimethoxyborohydride, Sodium Triacetoxyborohydride, Sodium Cyanoborohydride, and Catecholborane have greatly expanded the scope and utility of these reductions well beyond the classic Wolff-Kishner and Clemmenson reductions, to become one of the mildest deoxygenation procedures known.

NaBH4 is an effective tosylhydrazone reducing agent when used in methanolic dioxane (NaBH(OMe)3 is most likely the active reducing species), acetic acid (NaBH(OAc)3 is most likely the active reducing species), and less commonly in isopropanol and DMF (eq 13).53

Selective formation of hydrazones (using a stoichiometric amount of tosyl hydrazide) in the presence of relatively hindered or deactivated ketones is easily achieved in high yield and, in the case of eq 13, the ketones are not reduced under the reaction conditions.54 Reductions occur between room temperature and 70 °C for most tosylhydrazones without epimerization of a-stereocenters.55 The reaction proceeds by reductive elimination of p-toluenesulfinate and extrusion of dinitrogen to form an alkyllithium, which is quenched by solvent. Use of NaBD4 in AcOH or AcOD allows for mono- and dideuterio incorporation.53c Catecholborane is an equally effective reducing agent.56

NaBH3CN has proved particularly serviceable for reducing tosylhydrazones that can be generated in situ, since iminium ions reduce much faster than carbonyl groups with this reagent.57 The reactions are usually carried out in acidic 1:1 DMF--sulfolane at 100 °C, but even milder conditions have been used,50b,58 providing products in fair to good yield.59

Reduction of a,b-unsaturated tosylhydrazones with the boron reagents gives 1,2-hydride delivery followed by extrusion of toluenesulfinic acid to give an allylic diazene. Note that this process gives a similar intermediate to that obtained by alkyl- and alkenyllithium addition to N-TBDMS tosylhydrazones (eqs 1 and 2). Thus, reduction of these systems gives allylic migration of the double bond independent of thermodynamic preference, and is an excellent means of deconjugating double bonds with an intervening methylene (eqs 14 and 15).60

The NaBH4/MeOH conditions do not give good yields in this process due to predominating Bamford-Stevens-type reactions.61 NaBH4 and NaBH3CN work equally well in AcOH but catecholborane is the best reagent for this transformation because 1,4-addition of hydride is minimal. Catecholborane adds axially to bridgehead enones and undergoes 1,5-sigmatropic reduction on the convex face to give cis-decalin systems with good selectivity.62

Miscellaneous.

Intramolecular 1,3-dipolar cycloadditions of intermediate diazoalkanes derived from tosylhydrazones have been conducted under Boron Trifluoride Etherate or aprotic Bamford-Stevens reaction conditions to give pyrazolines and related compounds.63,30a [4 + 2] Cycloadditions of a,b-unsaturated aldehyde tosylhydrazones gave low yields of dihydropyridines.64 1,2-Enone transpositions have been described using vinylsilanes and vinyl sulfides.65 Tosylhydrazones may also be converted into alkyl hydroperoxides via a two-step procedure.66

Related Reagents.

2,4-Dinitrobenzenesulfonylhydrazide; Mesitylenesulfonylhydrazide; 2,4,6-Triisopropylbenzenesulfonylhydrazide.


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A. Richard Chamberlin & James E. Sheppeck II

University of California, Irvine, CA, USA



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