Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion

Abstract

A method for the conversion of pyrimidines into pyrazoles by a formal carbon deletion has been achieved guided by computational analysis. The pyrimidine heterocycle is the most common diazine in FDA-approved drugs, and pyrazoles are the most common diazole. An efficient method to convert pyrimidines into pyrazoles would therefore be valuable by leveraging the chemistries unique to pyrimidines to access diversified pyrazoles. One method for the conversion of pyrimidines into pyrazoles is known, though it proceeds in low yields and requires harsh conditions. The transformation reported here proceeds under milder conditions, tolerates a wide range of functional groups, and enables the simultaneous regioselective introduction of N-substitution on the resulting pyrazole. Key to the success of this formal one-carbon deletion method is a room-temperature triflylation of the pyrimidine core, followed by hydrazine-mediated skeletal remodeling.

Figure 1.

(A) Original disclosure of the hydrazine-mediated contraction of pyrimidine to pyrazole. (B) Summary of present disclosure.

Figure 2.

(A) Conceptual outline of peripheral and skeletal editing strategies. (B) Peripheral edits available about the pyrimidine heterocycle, including its use as a directing group for C–H functionalization. (C) Peripheral edits available for pyrazoles, noting its key inability to direct C–H functionalizations. (D) Rationale behind the poor directing group strength of pyrazoles relative to pyrimidines. ^a ωB97x-D, 6–31G(d,p). (E) Conceptual outline to leverage both peripheral and skeletal editing to access C–H functionalized pyrazoles.

Figure 3.

Mechanism of the triflylation-promoted, hydrazine-mediated ring contraction of pyrimidines. (A) Competitive detriflylation of B. (B) Calculations for aminal collapse pathway. (C) X-ray crystal structure of N-methyl-4-phenylpyrimidinium iodide (MeCN molecule omitted for clarity). (D) Fukui nucleophilicity (left) and electrophilicity (right) indices for A and B, respectively.

Figure 4.

Ring contraction scope. Reactions performed on 0.10 mmol of substrate. Percentages reported are isolated yields. (A) Scope of substrates substituted with arenes and heteroarenes at C4. (B) Scope of substrates substituted at C5. ^aTriflylation stage run at 60 °C for 2 h before the reaction mixture was cooled to 35 °C for the addition of hydrazine. (C) Scope of hydrazines. ^CHydrochloride salt of hydrazine derivative was used together with 4.0 equiv of Na₂ CO₃. ^dThe products were isolated as a 3:1 N2/N1 substitution mixture.

Figure 5.

(A,B) Scope of specialized substrates. ^a3.0 equiv Tf₂O was employed together with 4.0 equiv Na₂ CO₃; the reaction mixture was stirred with 10.0 equiv aqueous NaOH in 2:1 1,4-dioxane:methanol (0.33M) at 23 °C after completion to affect detriflylation. ^bThe basic workup step was omitted. (C) Scope of druglike substrates. ^cThe reaction was run at 60 °C. ^dHFIP was used as the reaction solvent, and triflylation was carried out at 0°C. (D) Synthesis of a C–H functionalized late-stage intermediate of Celecoxib. (E) Demonstrative pyrimidine-directed C–H functionalization reactions.