A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

The acylation of the acetonitrile anion with lactones and esters in ethereal solvents was successfully exploited using inexpensive KOt-Bu to obtain a variety of β-ketonitriles and trifunctionalized building blocks, including useful O-unprotected diols. It was discovered that lactones react to produce the corresponding derivatized cyclic hemiketals. Furthermore, the addition of a catalytic amount of isopropanol, or 18-crown-6, was necessary to facilitate the reaction and to reduce side-product formation under ambient conditions.

(DCM) were distilled over calcium hydride, whereas THF was distilled over sodium with benzophenone as an indicator. 2-Methyltetrahydrofuran (2MeTHF) and methyl tert-butyl ether (MTBE) were pre-dried over molecular sieves (4 Å) but not distilled prior to use. All the required chemicals or reagents were obtained from Sigma-Aldrich or Merck, Acros Organics or Fluka, and were used without further purification.
Normal chromatography was performed on silica (SiO2) gel 60 (Macherey-Nagel, particle size 0.063-0.200 mm), employing both isocratic and gradient eluent systems. Thin layer chromatography (TLC) of the compounds was executed either on Macherey-Nagel Alugram SiO2 G/UV254 plates pre-coated with 0.25 mm silica gel 60 or on Merck TLC silica 60 F254 plates. The TLC plates were viewed under UV light (254 nm and 366 nm).
Nuclear magnetic resonance (NMR) spectra were recorded on either a Bruker AVANCE 300 MHz, or a Bruker AVANCE III 500 MHz spectrometer. All spectra were recorded in [D]chloroform (CDCl3). Chemical shift values (δ) are reported in parts per million referenced against the signal of residual solvent (CDCl3: δ1H = 7.26 ppm, δ13C = 77.16 ppm). Coupling constants (J values) are given in hertz (Hz).
Melting points were determined on a Reichert hot-stage microscope, and remain uncorrected. All crystalline compounds were recrystallized in the appropriate solvents prior to melting point determination.
High resolution mass spectra (HRMS) were obtained with a Bruker compact mass spectrometer. The sample was dissolved in methanol to a concentration of 1 ng/μL and introduced by direct infusion. The ionization mode was electrospray (ESI), positive ion mode with a capillary voltage of 4500 V and a desolvation temperature of 180 °C using nitrogen gas at 4.0 L/min. δ-Valerolactone (3, 75%, 2.87 g, 21.5 mmol) was dissolved with stirring for 5 min in technicalgrade THF containing ca. 0.2% moisture (90 mL). Powdered KOt-Bu (95%, 5.08 g, 43 mmol) was added and the mixture was left stirring for 1 h under air. After adding MTBE (10 mL) and cooling on an ice bath, saturated NH4Cl (50 mL) was added. The reaction was quenched by adding water (150 mL), followed by EtOAc (100 mL) and 12 M aq. HCl (3.2 mL). Layers were separated, the organic layer was washed with brine (50 mL), dried (MgSO4) and the solvents evaporated in vacuo to afford a crude viscous oil product, the 1 H NMR spectrum of which is shown on p. 9. Using THF as solvent with 0.2 equiv IPA added :

Experimental procedures and compound characterisation
Starting from 3.8 g δ-valerolactone (3, 75%, 28.5 mmol), the procedure was carried out exactly as set out above, except that THF was used as the solvent. The 1 H NMR spectrum of the crude product obtained S4 here is shown below in this document for comparison to that obtained by using 2MeTHF as solvent. After column chromatography as before, pure hemiketal 5 (1.12 g, 28%) was obtained as colorless yellow oil.

Synthesis of hemiketal 6
The same procedure as described for hemiketal 5 was followed, except THF was used as the solvent.
After cooling on an ice-bath, sat. NH4Cl (20 mL) and EtOAc (20 mL) were added. After warming to rt, the layers were separated and the organic layer was washed with brine (10 mL), dried (MgSO4) and solvents evaporated in vacuo to yield crude diol product, which was purified by SiO2 gel chromatography (EtOAc) to yield 1 (898 mg, 100%) as viscous, colorless oil. Rf = 0.10 (75% EtOAc/hexane);  3.12 g, 26.4 mmol) was added over 1 min at rt and the mixture was left stirring for 30 min. After adding MTBE (10 mL) and cooling on an ice bath, saturated NH4Cl (50 mL) was added. After warming to rt and stirring for another 5 min, the layers were separated in a separatory funnel. The organic phase was washed with brine (50 mL). The combined aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layer was dried (MgSO4), filtered and evaporated to yield 1.39 g of crude hemiketal 6, which was dissolved in 2MeTHF (32 mL) and MeOH (8 mL) and cooled to 0 °C on an ice-bath. LiBH4 (0.26 g, 11.9 mmol) was added, the mixture was warmed to rt and stirred for 18 h. After work-up (see procedure for diol 1 above), and purification as in Procedure A, diol 8 (591 mg, 20% over 2 steps) was obtained.