Enantioseparation and racemization of α‐aryl‐α‐fluoroacetonitriles

Abstract

The 2‐Aryl‐2‐fluoroacetonitriles have garnered increasing interest as versatile building blocks in asymmetric synthesis. However, the configurational stability of these organofluorines is poorly understood and analytical methods that can be used to differentiate between their enantiomers remain underdeveloped. In this study, baseline high performance liquid chromatography (HPLC) enantioseparation of ten 2‐aryl‐2‐fluoroacetonitriles was achieved by screening frequently used chiral stationary phases. While Chiralcel OD, Chiralpak AD, and Chiralpak AS proved to be most broadly useful, preparative separation of the enantiomers of 2‐(2‐naphthyl)‐2‐fluoroacetonitrile was possible on Chiralcel OJ. This enabled racemization studies at various temperatures and in the presence of organic bases which showed that this compound is configurationally stable under neutral conditions upon heating to 130°C for 6 h but undergoes complete racemization within 10 h in the presence of stoichiometric amounts of a guanidine base at room temperature. The racemization is likely to proceed via formation of an achiral keteniminate intermediate and obeys reversible first‐order reaction kinetics with a half‐life time of 87.7 min in ethanolic hexanes at 23.2°C. Racemization is significantly slower and occurs with a half‐life time of 23.1 h at 22.4°C when the guanidine is replaced with a weaker amidine base.

Selective Csp3–F Bond Functionalization with Lithium Iodide

“…Having established a profound interest in organofluorine chemistry, 32 33 34 35 36 37 38 39 40 including C–F bond activation methodology and synthetic or chiroptical sensing applications thereof, 19,21 , 41–43 we decided to investigate the possibility of practical alkyl fluoride to iodide conversion, which would also enable subsequent nucleophilic displacements or other reactions. Hilmersson and co-workers showed that this is possible with YbI 3 (THF) 3 , which has to be prepared from expensive ytterbium(II) iodide (Scheme 1 ).…”

“…R f = 0.4 (hexanes/EtOAc, 4:1). The spectroscopic data of 2-(benzo[d]oxazol-2-ylthio)acetonitrile (40) are in accordance with the literature. 69…”

“…[4][5][6][7][8][9][10][11][12] In addition, several laboratories, including ours, have been able to demonstrate carbon-fluoride bond functionalization with unactivated aliphatic substrates although the need for harsh conditions, together with low functional group tolerance and competing side reactions continue to limit the general scope in some cases. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Scheme 1 C-F Bond functionalization with metal iodides 49 Having established a profound interest in organofluorine chemistry, [32][33][34][35][36][37][38][39][40] including C-F bond activation methodology and synthetic or chiroptical sensing applications thereof, 19,21,[41][42][43] we decided to investigate the possibility of practical alkyl fluoride to iodide conversion, which would also enable subsequent nucleophilic displacements or other reactions. Hilmersson and co-workers showed that this is possible with YbI 3 (THF) …”

Enantioseparation and racemization of 3‐fluorooxindoles

“…To this end, we recently investigated the racemization kinetics of 2-aryl-2-fluoroacetonitriles and developed catalytic asymmetric allylic alkylation and stereodivergent Mannich reactions with this emerging class of compounds. [10][11][12] Following our continuous interest in chiral organofluorines, [13][14][15][16][17][18][19][20][21][22][23][24] we now wish to disclose the results of a racemization study with 3-fluorooxindoles, which are frequently employed in catalytic asymmetric reaction developments and represent an important pharmacophore encountered in the potassium channel modulator Maxipost and other biologically active compounds. 25,26 Semipreparative chiral HPLC enantioseparation of the oxindoles 1-5 shown in Figure 1 using a Whelk-O 1 or Chiralpak IB column produced highly enantioenriched samples that were subjected to catalytic or stoichiometric base amounts at room temperature.…”

Catalytic Asymmetric Allylic Alkylation with Arylfluoroacetonitriles

“…By contrast, few reports on catalytic asymmetric aldol-type reactions with α-fluoro-α-arylacetonitriles devoid of an activating carbonyl group have appeared, Scheme . The scarcity of enantioselective carbon–carbon bond formation with arylfluoroacetonitriles can probably be attributed to the relatively low C–H acidity which hinders generation of a nucleophilic intermediate under mild reaction conditions, the general difficulty to control the stereofacial orientation of α-fluoronitrile carbanions, and complications that arise from side reactions including decomposition or HF elimination of fluoroacetonitriles in the presence of base …”