Direct α-Imination of N-Acyl Pyrazoles with Nitrosoarenes

Abstract

Unprecedented α-imino N-acyl pyrazoles were efficiently and selectively prepared through the 1,5,7-triazabicyclo[4.4.0]­dec-5-ene (TBD)-catalyzed reaction of nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol reaction/dehydration sequence. The α-imino acyl pyrazoles were demonstrated to be new versatile intermediates for practical one-pot syntheses of α-imino amides, dipeptide precursors, esters, and β-amino alcohols. The synthetic method competes with known protocols in terms of ready availability of the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the α-imino acid derivatives achievable.

Nitrone/Imine Selectivity Switch in Base‐Catalysed Reaction of Aryl Acetic Acid Esters with Nitrosoarenes: Joint Experimental and Computational Study

“…Hence, all the data suggest that radical pathways are not involved during the reaction. According to experimental data, literature precedents and our own report, [18] we suggest a mechanistic proposal for the reaction of aryl acetic acid esters and nitrosobenzene catalyzed by BEMP ( Figure 1).…”

“…In order to assess our hypothesis, we started the study by reacting commercially available phenyl acetic acid methyl ester with nitrosobenzene, under previously optimized reaction conditions, [18] in the presence of 10 mol% 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD) and 3 Å molecular sieves, at room temperature in CH 2 Cl 2 (Table 1, entry 1).…”

“…Within this framework, our previous results, achieved in the selective α-imination of acyl pyrazoles derived from aryl acetic acid, are also rationalized. [18] In those cases, the pyrazole ring raises the acidity of the H α to an extent where the E1 CB pathway is always energetically preferred, likewise in the case of the 1,3-dicarbonyl compounds presented above.…”

“…Our methodology provided an effective αimination of acyl pyrazoles, working under mild conditions and using a catalytic amount of base (Scheme 1 C). [18] High chemical selectivity toward imines observed, although traces of nitrones were occasionally detected, when using compounds less prone to enolate formation. Intrigued by this observation, we questioned whether a similar approach could be applied to access ketonitrones, by reacting easily available aryl acetic acid esters, which are notoriously less acidic at the αposition than the corresponding acyl pyrazoles (Scheme 1 D).…”

“…This process, whose mechanism is still unclear, usually proceeds under basic catalysis, yielding imines or nitrones in a ratio that is difficult to predict. Our methodology provided an effective α‐imination of acyl pyrazoles, working under mild conditions and using a catalytic amount of base (Scheme 1 C) [18] …”