A [2 + 2] Cycloaddition Route to Dimethylaminomethylene Vinamidinium Salts

Abstract

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).

One-Pot Synthesis of Tetraazamacrocyclic Complexes from the Arnold Salt

“…1 2+ (PF 6 -) 2 is a relatively safe, non-hygroscopic, crystalline material with a well-determined stoichiometry and non-coordinating counterions. The salt was reported by Davies, 15 who obtained it as a relatively pure crude product of Vilsmeier-Haack formylation of 3,3,3-trifluoropropanoic acid or vinamidinium salt. Another procedure based on formylation of bromocacetic acid, 17 calls for a time-consuming removal of DMF excess, by vacuum distillation of a highly corrosive reaction mixture.…”

“…13 Consequently, salts with safer ions were later proposed, namely tetrafluoroborate (hygroscopic) 14 and hexafluorophosphate. 15 Most recently, a stable and nondeliquescent salt of protonated Arnold trication and mixed chlorine/bromine counterions was also obtained. 16 For many applications, bis(hexafluorophosphate) Arnold salt is an appropriate TFM source.…”

“…We improved the synthesis of 1 2+ (PF 6 -) 2 by carrying out the reaction without DMF excess, and by elimination of the cooling step. Similarly to Davies, 15 we mixed the reagents (bromoacetic acid, DMF, POCl 3 ) gradually, without cooling. Addition with cooling, recommended in older recipes, triggers a risk of POCl 3 build-up followed by thermal runaway.…”

“…The analytical data for 1 2+ (PF 6 -) 2 agree with those reported previously. 15 1 H NMR (CD 3 CN, 200 MHz): δ = 8.03 (s, 3 H, =CH), 3.53 and 3.40 (2 × s, 2 × 9 H, CH 3 ).…”

Synthesis of 2-arylamino-5-formyl-pyrimidines from the bis(hexafluorophosphate) Arnold salt

“…1,2 Afterwards, other Arnold salts were prepared and reported, including tetrafluoroborate salt 1c , 3,4 hexafluorophosphate salt 1d and mixed chlorine/bromine trihalide salts. 5,6 These dimethylaminomethylene vinamidinium salts can serve as important three-carbon building blocks for preparing a wide array of carbocycles and heterocycles. 7 2-Arylaminopyrimidines are found in many biologically active natural products and also serve as components of a number of prominent commercial drugs, such as imatinib, nilotinib, pazopanib and rilpivirine (Figure 2).…”