Di-tert-Butyl azodicarboxylate: Synthesis & Applications

Di-tert-butyl azodicarboxylate (DBAD) is a widely utilized reagent in modern organic synthesis, valued for its ability to facilitate a range of chemical transformations under mild. conditions. Its primary application lies in the Mitsunobu reaction, where, in conjunction with a phosphine, it enables the conversion of alcohols to a variety of other functional groups with inversion of stereochemistry. Beyond the Mitsunobu reaction, Di-tert-Butyl azodicarboxylate serves as a potent electrophilic nitrogen source in amination reactions, particularly for the α-functionalization of carbonyl compounds. The synthesis of nitrogen-containing heterocyclic compounds, which are prevalent in many biologically active molecules, can also be achieved using DBAD.

Thermal decomposition mechanism and hazard assessment of di-tert-butyl azodicarboxylate

Azodicarboxylates belong to a class of azo compounds with ester groups. The azo double bond connecting the ester group is electrophilic and is an excellent electrophile and zwitterionic reagent. The prevailing ones are diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD) and di-tert-butyl azodicarboxylate (DBAD), etc.. Currently, Azodicarboxylates are usually applied as reactive intermediates to synthesize other macromolecular substances due to its unique structural characteristics, and the most widely used reaction is the Mitsunobu reaction. The commonly used DEAD and DIAD are required to be dissolved in solvents because of the above-mentioned thermal safety requirement, which brings difficulties to the separation of subsequent products and by-products; in order to solve the problem, some researchers are starting to pay attention to di-tert-butyl azodicarboxylate. It is a water-insoluble yellow crystalline reagent with a melting point in the range of 89–92 °C, and rather sensitive to light. However, the previous researches on the thermal hazard of DBAD are still very lacking. Therefore, in order to provide reasonable suggestion and effective strategy for the safety of DBAD, we use C80 micro-calorimeter and STA-MS-FTIR combined equipment to study the decomposition behavior and thermal mechanism of DBAD, thereby evaluating its thermal hazard through the SADT.[1]

Before using C80 to measure the thermal decomposition characteristics of di-tert-butyl azodicarboxylate, C80 was first calibrated by measuring the melting point of dibenzyl azodicarboxylate. The results showed that the melting point of dibenzyl azodicarboxylate at 0.5 °C min−1 was 46.61 °C (u(T) = 0.01 °C), which was consistent with its CAS data 43 ~ 47 °C.  DBAD has a single exothermic peak after endothermic melting, and the exothermic heat per unit mass ∆H is 699.85 ± 52.88 kJ kg−1; the activation energy range of DBAD is 28.58 kJ mol−1–52.03 kJ mol−1 calculated by Friedman differential method. The Malek method is used to determine the reaction mechanism function of the di-tert-butyl azodicarboxylate decomposition reaction as the Zhuralev-Lesokin-Tempelman equation. The reaction progress of 0–0.2 is controlled by the phase interface reaction, and the reaction progress 0.2–1.0 is controlled by diffusion and mass transfer process. The thermal decomposition mechanism of DBAD is as follows: firstly, the C–O single bond at (1) cracks, and ·C(CH3)3 separates out, then the C–C single bond cracks, releasing a large number of ·CH3+ particles; subsequently, the N=N double bond, the C–O single bond at (2) and the C–N single bond at (3) crack, particles: N–CO, ·O–CO–N:, HO–CO–N: and ·N=N–CO separate out, and these particles gradually decompose or oxidize to ·CH=CHCH3, ·O–CO/CO2 and ·COOH, etc.; eventually, these particle fragments are decomposed or oxidized into H2O, CO2, and N2, etc. Based on Semenov model, the SADT and TNR values of di-tert-butyl azodicarboxylate are 63.95 °C and 71.07 °C, relatively, under a standard package of 25 kg.

A Variation on the Fischer Indole Synthesis

In a new variation on the Fischer indole synthesis, readily available haloarenes are converted into a wide range of indoles in just two steps by halogen–magnesium exchange and quenching with di-tert-butyl azodicarboxylate, followed by reaction with aldehydes or ketones under acidic conditions. The protocol, which is readily extended to the preparation of indole isosteres, 4- and 6-azaindoles and thienopyrroles, obviates the need to prepare potentially toxic aryl hydrazines, simultaneously avoiding undesirable anilines such as naphthylamines. In planning a straightforward route from haloarenes to aryl hydrazines, and hence indoles, we were attracted by the use of di-tert-butyl azodicarboxylate as a source of the hydrazine unit, since the ensuing Boc-protecting groups would undergo concomitant cleavage under the Brønsted or Lewis acidic conditions of the Fischer cyclization. Such a method would complement and extend other routes from haloarenes to aryl hydrazine derivatives that have been developed recently, starting a decade ago with Hartwig’s palladium-catalyzed coupling of bromobenzenes with benzophenone hydrazone. Almost simultaneously, Buchwald and co-workers reported a similar Pd-coupling to benzophenone hydrazone.[2]

Synthesis of Aryl Hydrazides from Aryl Iodides: An oven-dried flask was cooled to room temperature under argon, charged with a solution of aryl iodide (1.0 mol equiv) in THF (4–20 mL/mmol), and then cooled to −20 °C. A solution of isopropylmagnesium chloride in THF (2.0 M; 1.1 mol equiv) was added dropwise over 5 min, and the resulting mixture was stirred at −20 °C for 1 h then 0 °C for 1 h (note that phenylmagnesium chloride was used for halides containing a nitro group). A solution of di-tert-butyl azodicarboxylate (1.3 mol equiv) in THF (4 mL/mmol) was added dropwise over 5 min at 0 °C, and the resulting mixture was stirred at 0 °C to room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL/10 mmol), diluted with water (50 mL/10 mmol), and extracted with ethyl acetate (3 × 40 mL/10 mmol). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Column chromatography of the residue gave the product. An oven-dried flask was cooled under argon to room temperature, and charged with a solution of 4-bromophenyl 4-toluenesulfonate (3.27 g, 10 mmol) in THF (20 mL). A solution of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF; 8.46 mL, 11 mmol) was added over 5 min, and the resulting mixture was stirred at room temperature for 6 h. The mixture was cooled to 0 °C, and a solution of di-tert-butyl azodicarboxylate (2.99 g, 13 mmol) in THF (20 mL) was added over 5 min. The mixture was stirred at room temperature for 1.5 h,and worked up as in the general procedure. The title compound was obtained in 76% yield.

Aerobic Oxidation of Di-tert-butyl Hydrazodicarboxylate to Di-tert-butyl Azodicarboxylate

Azodicarboxylates such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and di-tert-butyl azodicarboxylate (DBAD) are very versatile reagents in organic synthesis. The representative utilization of azodicarboxylates is Mitsunobu reaction. The combination of DEAD and triphenylphosphine causes condensation reaction between carboxylic acids and alcohols to produce the corresponding esters. In addition, azodicarboxylates have been used in electrophilic amination. In conclusion, we revealed that CuI/DMAP was able to catalyze the aerobic oxidation of DBAD-H2 to DBAD. By using this aerobic oxidation, we developed a CuI and Di-tert-Butyl azodicarboxylate co-catalytic system for the aerobic dehydrogenation of 1,2,3,4-tetrahydroquinolines to afford quinolines under mild conditions. A variety of 1,2,3,4-tetrahydroquinolines underwent dehydrogenation in the presence of a catalytic amount of CuI, DBAD, and DMAP to produce the corresponding quinolines; however, the use of DIAD and 4-methoxypyridine, instead of DBAD and DMAP, was effective for the dehydrogenation of sterically hindered substrates. Further mechanistic studies and other applications, especially for the Mitsunobu reaction using a catalytic amount of azodicarboxylate, are now under investigation.[3]

References

[1]Jia, M., Guo, S., Chen, S. et al. Thermal decomposition mechanism and hazard assessment of di-tert-butyl azodicarboxylate (DBAD). J Therm Anal Calorim 148, 4317–4331 (2023).

[2]Inman, Martyn et al. “Two-step route to indoles and analogues from haloarenes: a variation on the Fischer indole synthesis.” The Journal of organic chemistry vol. 77,3 (2012): 1217-32. doi:10.1021/jo201866c

[3]Inman, M., Carbone, A., & Moody, C. J. (2011). Two-step route to indoles and analogues from haloarenes: A variation on the Fischer indole synthesis. The Journal of Organic Chemistry, 77(3), 1217–1232.

You may like