(Z)-Selective Takai olefination of salicylaldehydes

The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly (Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of related substrates led to the identification of key factors responsible for this surprising inversion of selectivity, and enabled the development of a modified mechanistic model to rationalise these observations.

Chemical shifts (δH) are quoted in parts per million (ppm), to the nearest 0.01 ppm, and are referenced to the residual non-deuterated solvent peak. Coupling constants (J) are reported in Hertz (Hz) to the nearest 0.1 Hz. Data are reported as follows: chemical shift, multiplicity (br = broad; s = singlet; d = doublet; t = triplet; q = quartet; quint = quintet; sept = septet; m = multiplet; or as a combination of these), coupling constant(s), integration, and assignment. The numbering/lettering on selected structures does not follow the IUPAC naming system and is used for the assignment of the 1 H NMR and 13 C NMR spectra. Proton assignments were determined either on the basis of unambiguous chemical shift, coupling pattern, by patterns observed in 2D experiments ( 1 H-1 H COSY, HMBC and HMQC) or by analogy to fully interpreted spectra for related compounds.
Carbon magnetic resonance spectra were recorded by broadband proton spin decoupling at ambient probe temperatures (unless otherwise stated) using an internal 191 deuterium lock on the following instruments: Bruker DRX-400 (100 MHz), Bruker Avance 400 QNP (100 MHz), Bruker Avance 500 Cryo Ultrashield (125 MHz), and Bruker BB ATM 500 (125 MHz). Chemical shifts (δC) are quoted in ppm, to the nearest 0.1 ppm, and are referenced to the deuterated solvent peak.
Assignment was based on chemical shift, DEPT editing and where appropriate, HMQC and HMBC experiments or by analogy to fully interpreted spectra of related compounds.

General procedure for the Takai olefination
A 15 mL vial was charged with a stir bar and 4 Å molecular sieves and oven dried. It was then stoppered and flushed with argon. To this was added CrCl 2 (150 mg, 1.22 S4 mmol, 6.0 equiv), which was weighed out under nitrogen. To this was added 4 mL of anhydrous THF and the suspension was cooled to 0 °C with stirring and bubbled through with argon. CHI 3

Synthesis and characterisation
The following molecules are fully characterised, because they were either able to be purified or yielded pure E or Z isomer in the Takai olefination.

2-Formylphenyl acetate (14)
To a solution of salicylaldehyde (0.768 mL, 7.24 mmol, 1 equiv) in DMF (7 mL) at 0°C was added sodium hydride (174 mg, 7.24 mmol, 1 equiv) in small portions. The mixture was stirred at rt for 10 minutes, then acetic anhydride (747 mg, 7.31 mmol, 1.01 equiv) was added dropwise. After stirring overnight, the mixture was poured onto a mixture of iced water and 1 N aqueous HCl (20 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL), then the combined organics were washed with NaHCO 3 (15 mL), water (15 mL), brine (15 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure, then the crude product was purified by flash chromatography using silica, eluting with 30% diethyl ether in hexane. Product was collected, along with what 1 H NMR revealed to be the dimethyliminium derivative of the product. This derivative was stirred overnight in a mixture of CH 2 Cl 2 (25 ml) and 1 N HCl (25 mL), then the aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organics were washed with water (15 mL) then dried (MgSO 4 ).

S6
Removal of solvent under reduced pressure yielded more product, which was combined with that produced earlier to yield a pale yellow liquid (0.372 g, 2.27 mmol, 31%). The data are consistent with those previously reported [2].

6-Iodosalicylaldehyde (28)
Sodium hydroxide (1.80 g, 46.0 mmol, 8.2 equiv) was dissolved in water (5 mL). 3-Iodophenol (1.23 g, 5.60 mmol, 1.0 equiv) was added and the mixture was heated to 75 °C. Chloroform (0.92 mL, 11.6 mmol, 2.1 equiv) was added and the resulting orange solution was stirred at 75 °C until reflux ceased (~45 m). After cooling to rt, the mixture was poured onto 3 N aqueous HCl (50 mL), followed by extraction with Takai olefination NMR data 1 H NMR and COSY data were obtained for all Takai olefination products. From COSY it was possible to correlate the two peaks of the alkene for each olefin isomer, and therefore incontrovertibly assign the alkene peaks. The aromatic ring peaks of the substrates largely overlapped with each other, and were unimportant to determination of E/Z ratio. Reported below is 1 H NMR data for one or both of the alkene peaks for each isomer, depending on whether both were clearly separated and therefore able to be integrated. Integral values are reported relative to the most deshielded alkene peak, and the E/Z ratios thereby determined. E/Z ratio: 1.01/0.13, or 89:11.
Crude NMR showed generation of only the E isomeric product from benzaldehyde; the corresponding Z isomer was undetectable.