Fluorohydration of alkynes via I(I)/I(III) catalysis

Substrate specificity is ubiquitous in biological catalysis, but less pervasive in the realm of small-molecule catalysis. Herein, we disclose an intriguing example of substrate specificity that was observed whilst exploring catalysis-based routes to generate α-fluoroketones from terminal and internal alkynes under the auspices of I(I)/I(III) catalysis. Utilising p-TolI as an inexpensive organocatalyst with Selectfluor® and amine/HF mixtures, the formation of protected α-fluoroketones from simple alkynes was realised. Whilst the transient p-TolIF2 species generated in situ productively engaged with pentynyl benzoate scaffolds to generate the desired α-fluoroketone motif, augmentation or contraction of the linker suppressed catalysis. The prerequisite for this substructure was established by molecular editing and was complemented with a physical organic investigation of possible determinants.


I. General Information
All chemicals were purchased as reagent grade and used as received unless otherwise stated. Solvents for extraction or purification were purchased as technical grade and distilled on the rotary evaporator prior to use (exception: Et2O was used as purchased).

Amine/HF mixtures
Amine/HF stock solutions were prepared as follows:

III. Synthesis of starting materials
General procedure C for the esterfication of acetyl chlorides with alkynols The corresponding alkynol (1.0 equiv) and acetyl chloride (1.1-2.0 equiv) were dissolved in Et2O, NEt3 (1.1-2.0 equiv) was added slowly, and the reaction mixture was stirred for the indicated time at ambient temperature. The reaction mixture was diluted with EtOAc and H2O, and the aqueous layer was extracted with EtOAc (3×).
The combined organic layers were washed with H2O and brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude mixture was purified by column chromatography.
Rf (n-pentane/ Analytic data in agreement with the literature [10].

N-(Pent-4-yn-1-yl)benzamide (S9)
According to a modified procedure [12], 2-(pent-4-yn-1yl)isoindoline-1,3-dione (16) (1.1 g, 5.0 mmol, 1.0 equiv) was dissolved in EtOH (13 mL). N2H4 (2.5 mL, 50 mmol, 10 equiv) was added to the slurry until it got clear and the reaction mixture was stirred for 3 h at 85 °C. Then, H2O was added, followed by a solution of HCl (2 M) to adjust a pH of 3. The precipitate was filtered and the filtrate was concentrated in vacuo. The residue was cooled to 0 °C and a solution of NaOH (10 M, 5 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×) and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Pent-4-yn-1-amine was used crude without any purification in the next step.
Then, the reaction mixture was poured into a saturated solution of NaHCO3 and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The yield was determined by 19 F NMR analysis of the crude reaction mixture using ethyl fluoroacetate as internal standard. Then, the crude reaction mixture was purified by column chromatography affording the desired product.

V. SAR analysis of score scaffold
General procedure E for SAR analysis of score scaffold The alkyne (0.2 mmol, 1.0 equiv) and p-TolI (8.7 mg, 40 μmol, 20 mol %) were dissolved in CHCl3 (0.5 mL) in a Teflon ® screw cap vial. H2O (3.6 µL, 0.2 mmol, 1.0 equiv), amine/HF 1:7.5 (0.5 mL), and Selectfluor ® (106 mg, 0.3 mmol, 1.5 equiv) were added, and the reaction mixture was stirred for 24 h at ambient temperature. The reaction mixture was poured into a saturated solution of NaHCO3 and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The yield was determined by 19 F NMR analysis of the crude reaction mixture using ethyl fluoroacetate as internal standard. The observed α-fluoroketones were assigned by analogy to previously reported α-fluoroketones in this paper.

S27
In addition, the obtained product was submitted to 13              R-values are given for observed reflections, and wR 2 values are given for all reflections.

X-ray crystal structure analysis of 2 (gil9678)
A colourless plate-like specimen of C12H13FO3, approximate dimensions 0.039 mm × 0.138 mm × 0.190 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. A total of 1105 frames were collected. The total exposure time was 18.11 hours. The frames were integrated with the Bruker SAINT software package using a wide-frame algorithm. The integration of the data using a monoclinic unit cell yielded a total of 15346 reflections to a maximum θ angle of 66.51°  probability.