4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications

A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.


Materials and Methods
General All metathesis reactions were performed under argon using Schlenk technique. Syntheses of starting materials: dienes and other compounds were performed under argon atmosphere unless otherwise stated. All glassware was dried overnight in an oven (135 °C). Analytical thin-layer chromatography (TLC) was performed using silica gel 60 F254 precoated plates (0.25 mm thickness, Merck) with a fluorescent indicator. Visualization of TLC plates was performed by KMnO4 aqueous solution and anisaldehyde/H2SO4 stain. The flash column chromatography was performed using Merck silica gel 60 (230-400 mesh) with n-hexane/ethyl acetate eluent system, unless otherwise stated. GC analyses were performed by means of PerkinElmer Clarus 580 chromatograph with FID detector and GL Sciences InertCap 5MS/Sil Capillary Column (Inner Diameter 0.25 mm, Length 30 m, df 0.50 μm). GC-MS analyses were performed by means of PerkinElmer Clarus 680 chromatograph with Mass Spectrometer Clarus SQ 8C detector and GL Sciences InertCap 5MS/Sil Capillary Column (Inner Diameter 0.25 mm, Length 30 m, df 0.50 μm). NMR spectra were recorded on Agilent 400-MR DD2 400 MHz spectrometer. NMR chemical shifts are reported in ppm with solvent residual peak as a reference (7.26 and 77.16 ppm for 1 H and 13 C in CDCl3). Deuterated chloroform was purchased from Eurisotop, stored over molecular sieves and used without further purification. The following abbreviations are used in reporting NMR data: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sex (sextet), sep (septet), m (multiplet), br (broad). 1 H NMR signals are given followed by multiplicity, coupling constants J in Hertz, and integration in parentheses.
Infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum One FTIR spectrometer with diamond ATR accessory, wave numbers are in cm -1 . Elemental Analyses (EA) were provided by the EA analytical laboratory at the Institute of Organic Chemistry, Polish Academy of Sciences (PAS). High Resolution Mass Spectra (HRMS) were provided by the Faculty of Chemistry University of Warsaw or analytical laboratory at the Institute of Organic Chemistry, PAS.
Preparation of anhydrous 4-MeTHP 4-Methyltetrahydropyran (4-MeTHP) was dried by distillation from sodium benzophenone ketyl: sodium wire and benzophenone was added to 4-MeTHP, and the mixture was heated at reflux (105 °C) under argon for 12 hours. After that time the solvents was distilled to an oven-dried ampoule and stored over 3A molecular sieves. The level of water in such prepared 4-MeTHP was 2 ppm as measured by Karl Fischer titrator.

Characterization of solvents
Solvents used for the RCM model reaction of 1 were commercially available, used without any purification either drying or degassing. The water content in each solvent was measured. All solvents were used soon after the bottle was opened unless otherwise stated. Next, peroxides content in two batches of THF was checked. Potassium iodide starch papers were dipped in a standard hydrogen peroxide solution (containing from 0 to 470 mg H2O2/kg) in water and left to dry out, to create the color-scale ( Figure S1). Using this scale peroxides concentration in THF2 can be roughly estimated to be much higher than the one in THF1. Figure S1. Peroxide color-scale (top) and THF1 and THF2 test results (bottom).
Model RCM reaction of diethyl diallylmalonate ( Figure 3) in different solvents A GC vial was charged with 1.3 mg (2 μmol, 1 equiv.) of Ru3d catalyst followed by 1 mL of 1 (0.1 M solution 0.1 mmol, 100 equiv.) in an appropriate HPLC grade, non-deoxygenated solvent. The vial was closed and mixed with shaking it for a few seconds. Next, the solution was quickly transferred to an NMR tube containing inside a sealed capillary with C6D6 solvent needed to lock and shim the sample. The tube was closed and transferred to an NMR apparatus to record spectra at 50 °C.

S5
RCM/Isomerization of N,N-diallyltosylamide (Figure 4) 4 mL vial closed with a screw cap was charged with appropriate ruthenium catalyst (2 μmol) followed by addition of 2.0 mL of the substrate (0.1 M solution, 0.2 mmol, 100 equiv.). The reaction mixture was stirred at 80 °C or 105 °C (boiling 4-MeTHP) for 1 h and next the ruthenium scavenger, SnatchCat, CAS: 51641-96-4 (2.3 mg, 10.g mmol, 4.4 equiv.) was added to stop metathesis/isomerization reactions, and the solution was stirred for additional 30 minutes. The content of the vial was transferred to 10 mL flasks, the solvent was evaporated under the reduced pressure, and the residue was analyzed by 1 H NMR. General procedure for ring-closing metathesis reactions Under argon atmosphere a preheated Schlenk-flask equipped with a Teflon-coated magnetic stirring bar and septum was charged with a 4-MeTHP solution of a diene. The desired amount of catalyst was added in a 4-MeTHP solution and the reaction mixture was stirred for a given time at 70 °C. The reaction progress was monitored by TLC. When full conversion was reached, SnatchCat solution (10 mg in 1 mL 4-MeTHP, 4 equiv. with respect to the catalyst) was added to stop the reaction. Volatiles were removed in vacuum and the crude product was purified by column chromatography.

S6
The spectra correspond to those described in the literature. The spectra correspond to those described in the literature. 4  The spectra correspond to those described in the literature. 7 1-(2,5-Dihydro-1H-pyrrol-1-yl)-2-(3-(2,2,3,3-tetramethylcyclopropane-1-carbonyl)-1H-indol-1yl)ethan-1-one (38) 1  The spectra correspond to those described in the literature. 8 General procedure for cross-metathesis reactions Under argon atmosphere a preheated Schlenk-flask equipped with a Teflon-coated magnetic stirring bar and septum was charged with corresponding substrate (1 equiv.) and cross partner (3 equiv.) dissolved in 4-MeTHP. The desired amount of catalyst was added and the mixture was stirred at 70 °C. When no reaction progress was observed another portion of catalyst was added to the reaction mixture. The reaction was stopped by addition of SnatchCat solution (10 mg in 1 mL $-MeTHP, 4 equiv. with respect to the catalyst). All volatiles were removed in vacuum and the crude product was purified by column chromatography.  3311, 3108, 2959, 2871, 1690, 1599, 1580, 1558,  1532, 1489, 1466, 1393, 1345, 1278, 1247, 1168, 1129, 1110, 1077, 1029, 928, 819, 738, 697, 675, 654, 618      ICP-MS measurements 125 mg of 42 was placed in preweighted polytetrafluoroethylene (PTFE) vessel and the weight of the filled vessel was recorded. A mixture of acids (7 mL of nitric acid and 1 mL of hydrochloric acid) and deionized distilled water (3 mL) was added to the vessel. The vessel was capped, stirred for 5 minutes, placed in a microwave reactor, and digested at few steps from 120 °C to 250 °C under a pressure of 20-60 bar (1 bar=1×105 Pa) for 50 min. After digestion, the vessel was cooled to room temperature and placed in ultrasonic bath to degas sample. Content of the vessel was quantitatively transferred without filtration to graduated flask and diluted to a final volume of 50 mL with high-purity deionized distilled water. Ruthenium concentration was determined by ICP-MS, calibrated by using commercially available standards. The concentration obtained from ICP-MS was multiplied by the dilution volume (50 mL) and divided by the calculated sample weight. Scheme S1: The influence of solvent on efficiency in RCM reaction of 41.
To a solution of 41 (10 g, 70 mmol) in DCE (200 mL) the catalyst (0.14 g, 1 mol%) was added under protective atmosphere of argon. The reaction mixture was stirred at 70 °C for 2 hours, until TLC monitoring showed complete conversion. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in 10% aqueous solution of NaOH (12 g/120 mL) at 80 °C, purified with activated charcoal (3 g), and precipitated by dropwise addition of concentrated HCl (30 mL). The reaction mixture was cooled down and the precipitated product was filtered and dried in vacuum drier. Product 42 was obtained as a cream solid (7.43 g, 79%).

A) Reaction mass efficiency
Reaction Mass Efficiency (RME) is the percentage of actual mass of the desire product to the mass of all reactants used.

×100
For RCM reaction performed in 4-MeTHP: RME = 27.17 g × 100 / 33 g = 82.3% For RCM reaction performed in DCE: RME = 7.43 g × 100 / 10 g = 74.3% The reaction mass efficiency is higher in the case of process performed in 4-MeTHP which makes it a more "green" approach. For RCM reaction performed in DCE: E = (10 g + 0.14 g + 250 g + 165 g -7.43 g) / 7.43 g = 56.22 (where 10 g is mas of 41, 0.14 g is mas of Ru3d, 250 g is mas of DCE, and 165 g is the sum of masses of solutions of NaOH and HCl) The environmental factor is lower for reaction performed in 4-MeTHP which makes it "green" approach.
S20 C) EcoScale score The EcoScale 20 allows the evaluation of the effectiveness of a reaction. It gives a score from 0 to 100, not only for yield, but also includes other parameters such as cost, safety, technical set-up, energy and purification aspects. EcoScale score 51 67 * Price calculated for 10 mmol reaction scale, prices obtained from Sigma Aldrich, TCI, and Combi Blocks (07.09.2020). ** As 41 is not commercially available its price was calculated based on cost of its preparation. Exact value is trade secret of Polpharma Pharmaceutical Works.