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. 2020 Dec 18;24(12):2953-2959.
doi: 10.1021/acs.oprd.0c00470. Epub 2020 Dec 4.

Development of a Scalable and Sublimation-Free Route to MTAD

Zohaib R Siddiqi  1 , Chad N Ungarean  1 , Tanner W Bingham  1 , David Sarlah  1
Affiliations

Development of a Scalable and Sublimation-Free Route to MTAD

Zohaib R Siddiqi et al. Org Process Res Dev. .

Abstract

The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation.

Keywords: 1,2,4-triazoline-3,5-dione; MTAD; arenophile; dienophile; urazole.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(A) Common methodologies employing MTAD and their applications. (B) First-generation route to synthesize urazole. (C) The work described herein.
Figure 2.
Figure 2.
(A) Preparation of 5. (B) Purification and separation of 5 and imidazole. (C) Optimization of cyclization: base (2.0 equiv), solvent (1.0 M), 5 (1.0 mmol). (D) Conditions to oxidize urazole: aTwo crops were collected. bReaction was performed on 0.09 mol scale. cDimethylmalonic acid was used as internal standard. dFrom 5.
Figure 3.
Figure 3.
(A) Scale-up conditions: step 1, ethyl carbazate (4) (1.0 equiv), carbonyldiimidazole (1.0 equiv), THF (1.0 M), 0 °C; MeNH2 (1.3 equiv, 40% aq), 0 °C to rt, 12 h; step 2, i-PrOH, two crops; step 3, 5 (1.0 equiv), K2CO3 (2.0 equiv), MeOH (1.0 M), 65 °C, 6 h; HCl (4.0 equiv, 12 M, aq); step 4, urazole (6) (1.0 equiv), t-BuOCl (1.05 equiv), EtOAc (0.75–1.0 M), 0 °C, 30 min. (B) Reaction vessel to yield 5. (C) Left, first crop filtration; middle, second crop filtration; right, 137 g of 5. (D) 20 g of MTAD produced in one step.
Figure 4.
Figure 4.
Comparison of MTAD purification procedures relative to a known reaction. Conditions: benzene (10 equiv), 1 (1.0 equiv), CH2Cl2, visible light, −78 °C; then [Ni(acac)2] (1.5 mol%), (R,Rp)-i-Pr-Phosferrox (2.0 mol%), 3,4-methylene dioxyphenylmagnesium bromide (2.5 equiv), CH2Cl2 THF, −78 to 25 °C; then Me2SO4, K2CO3.
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