A New Color of the Synthetic Chameleon Methoxyallene: Synthesis of Trifluoromethyl‐Substituted Pyridinol Derivatives: An Unusual Reaction Mechanism, a Remarkable Crystal Packing, and First Palladium‐Catalyzed Coupling Reactions

Abstract

Addition of lithiated methoxyallene to pivalonitrile afforded after aqueous workup the expected iminoallene 1 in excellent yield. Treatment of this intermediate with silver nitrate accomplished the desired cyclization to the electron-rich pyrrole derivative 2 in moderate yield. Surprisingly, trifluoroacetic acid converted iminoallene 1 to a mixture of enamide 3 and trifluoromethyl-substituted pyridinol 4 (together with its tautomer 5). A plausible mechanism proposed for this intriguing transformation involves addition of trifluoroacetate to the central allene carbon atom of an allenyl iminium intermediate as crucial step. Enamide 3 is converted to pyridinol 4 by an intramolecular aldol-type process. A practical direct synthesis of trifluoromethyl-substituted pyridinols 4, 10, 11, and 12 starting from typical nitriles and methoxyallene was established. Pyridinol 10 shows an interesting crystal packing with three molecules in the elementary cell and a remarkable helical supramolecular arrangement. Trifluoromethyl-substituted pyridinol 4 was converted to the corresponding pyridyl nonaflate 13, which is an excellent precursor for palladium-catalyzed reactions leading to pyridine derivatives 14-16 in good to excellent yields. The new synthesis of trifluoromethyl-substituted pyridines disclosed here demonstrates a novel reactivity pattern of lithiated methoxyallene which is incorporated into the products as the unusual tripolar synthon B.

Highly Functionalised Enantiopure 4‐Hydroxypyridine Derivatives by a Versatile Three‐Component Synthesis

“…The combined organic layers were washed with saturated aqueous NaHCO 3 solution and brine and dried with anhydrous Na 2 SO 4 , filtered followed by removal of the solvent under reduced pressure. The crude material was purified by flash column chromatography on silica gel (eluent: hexane/ethyl acetate 50:50 to 30:70 as linear gradient) to afford 8 as a yellow oil; yield: 201 mg (51%); [a] 9,À4.7,18.2,25.8 (2q,s,q,TBS),28.5,35.3 (q,s,58.8 (q,OMe),73.4 (d,113.9 (d,126.4,128.7,128.9,140.9 (3d,s,Ph),145.6,146.7,147.1 (3 s, Si (401.6): C 68.78,H 8.78,N,3.49;found: C 68.48,H,8.84,N 3.55. Typical Procedure for the Esterification of 4-Hydroxypyridines with (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl Chloride -methoxypyridin-4-yl 3,3,3-trifluoro-2-methoxyphenylpropanoate (18): 22 mg (0.06 mmol) of 8 and 17 mL (0.09 mmol) of (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride were dissolved in 0.3 mL of pyridine and 0.3 mL of CH 2 Cl 2 and stirred at ambient temperature overnight. After complete consumption of the starting material (as indicated by TLC) H 2 O was added, the organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 .…”

“…[9] As shown in Scheme 1, a mixture of enamides and the desired 4-hydroxypyridines is formed in this process. Subsequent treatment of the crude product with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and triethylamine induces an intramolecular Mukaiyamatype aldol reaction to convert the remaining enamide intermediates into the corresponding 4-hydroxypyridines.…”

“…[9] We were now interested to expand the scope of this unique transformation by incorporation of chiral acids and nitriles.…”

“…On the basis of three representative compounds, it was possible to show that carboxylic acids and nitriles with a-secondary stereogenic centres do not undergo racemisation under the employed conditions. The coordination chemistry of these compounds -which should be prone to fine tuning of their properties by employing the two oxy functionalities [9] -and their application as ligands in asymmetric transition metal-catalysed processes are under investigation.…”

Transition Metal‐Catalyzed Synthesis of Monocyclic Five‐Membered Aromatic Heterocycles

“…Iminoallene 209, possessing a tert-butyl substituent, under Marshalls conditions with 20 mol% of AgNO 3 underwent cycloisomerization to give 2,3-disubstituted pyrrole 210 in moderate yield (Scheme 8.77) [266]. It should be mentioned that other iminoallenes were either completely inefficient in this transformation or provided inferior yields of the corresponding pyrroles, probably due to the high iminoallene instability.…”