4-Phenyl-1,2,4-triazoline-3,5-dione1

[4233-33-4]  · C8H5N3O2  · 4-Phenyl-1,2,4-triazoline-3,5-dione  · (MW 175.16)

(highly reactive dienophile and enophile)

Alternate Names: PTAD; N-phenyl-1,2,4-triazoline-3,5-dione.

Physical Data: mp 179 °C (dec).2

Form Supplied in: PTAD and 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) [13274-43-6]) are widely available commercially.

Preparative Methods: there are several reported preparations,2 -9 particularly for the in situ preparation.

Handling, Storage, and Precautions: normal precautions against exposure to moisture and air; reacts with alcohols and water.

Diels-Alder Cycloaddition Reactions.

4-Substituted 1,2,4-triazoline-3,5-diones (e.g. PTAD and MTAD) are exceptionally reactive dienophiles and are more reactive than good dienophiles such as Maleic Anhydride, N-Phenylmaleimide, Diethyl Azodicarboxylate, and Dimethyl Acetylenedicarboxylate. For example (eq 1), PTAD reacts rapidly with Cyclopentadiene without a catalyst at -78 °C and with 1,3-Butadiene at -50 °C.10-12

Given the facility with which PTAD undergoes [4 + 2] cycloaddition, mechanistic aspects of its reaction have been extensively studied,13,14 and PTAD has become the classic reagent for probing the reactivity of weak Diels-Alder dienes. For example (eq 2), 1,3,5-Cycloheptatriene reacts via its norcaradiene isomer to afford the PTAD [4 + 2] cycloadduct.15-17 Cyclooctatetraene,18 styrenes,19 and 2-vinylindoles20 also undergo [4 + 2] cycloaddition with PTAD.

The synthetic utility of PTAD [4 + 2] cycloadducts has been relatively modest. The cycloadducts have been used in the synthesis of certain piperazic acids.21 The PTAD group can be removed from the cycloadduct by treatment with Lithium Aluminum Hydride,22 Potassium Carbonate in DMSO,23 refluxing 1,1,3,3-Tetramethylguanidine,24 and Potassium Hydroxide in 95% ethanol.9 Thus PTAD can be considered as a protecting group for 1,3-dienes. For example (eq 3), Barton and co-workers9 reported that ergosterol reacts with PTAD in near-quantitative yield and the diene can be regenerated from the cycloadduct by treatment with 2.1 N KOH in 95% ethanol (1.5 h, 65 °C, 98%).

PTAD cycloadducts can be converted to the corresponding azoalkanes via hydrolysis and subsequent oxidation, and in some cases this offers advantages over the use of diethyl azodicarboxylate. For example, Adam and co-workers25 reported the preparation of the bicyclic azoalkane shown in eq 4 in good yield from the PTAD cycloadduct. More commonly PTAD [4 + 2] cycloadducts have found use as a tool for structure elucidation via classical chemical reactivity,26,27 crystallographic,19,28-30 or mass spectral analysis.31,32

Ene Reactions.

PTAD and other 4-substituted 1,2,4-triazoline-3,5-diones are exceptionally reactive enophiles, PTAD reportedly being some 104 times more reactive than diethyl azodicarboxylate in the reaction with cyclohexene (eq 5).33,34 The ene reactions of PTAD with alkenes35-39 and enones40,41 have been the subject of several mechanistic investigations.

PTAD reacts with b-diketones and b-keto esters to afford novel 1:1 and 2:1 adducts, perhaps via an ene pathway involving the enol form of the b-dicarbonyl compound. For example (eq 6), PTAD reacts with 2,4-Pentanedione to give the 2:1 adduct in 95% yield.42

The reactions of allylsilanes,43-45 -germanes,45 and -stannanes46 with PTAD partition between ene and metallo-ene pathways. For example, the allylsilane43 in eq 7 undergoes ene reaction with PTAD to afford the adduct in 95% yield, while the allylstannane46 in eq 8 undergoes predominantly metallo-ene reaction with PTAD. Silyl enol ethers and PTAD condense with O- to N-silyl transfer to afford a-amino ketone derivatives.47 PTAD can participate in the relatively rare acyl-ene reaction.48

Miscellaneous Reactions.

PTAD has been used as an efficient trap for certain reactive intermediates, including radical species49 and disilirane.50 PTAD can effect the oxidation of certain alcohols51 and sulfides52 and MTAD has been employed for the mild oxidation of a hydrazine to the corresponding diazene.52b PTAD reacts with electron-rich alkenes or aromatic rings to give dipolar intermediates,53-55 and with Ethyl Diazoacetate to afford the unusual cycloadduct shown in eq 9.56,57

PTAD undergoes [2 + 2] cycloaddition with Diphenylketene58 and certain alkenes.59,60 Strained ring systems often undergo unusual cycloaddition modes with PTAD. For example, the strained bicycloalkene in eq 10 affords the rearranged urazole in 95% yield,61,62 and the alkenylidenecyclopropane shown in eq 11 affords the bicyclic structure.63,64

Related Reagents.

Diethyl Azodicarboxylate.


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James M. Takacs

University of Nebraska-Lincoln, NE, USA



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