Transition‐Metal‐Free Reductive Hydroxymethylation of Isoquinolines

Abstract A transition‐metal‐free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4‐quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro‐type reduction followed by an Evans–Tishchenko reaction. When isoquinolines featuring a proton at the 4‐position are used, a tandem methylation‐hydroxymethylation occurs, leading to the formation of 2 new C−C bonds in one pot.


3-Phenyl-4-methylisoquinoline (S8)
The title compound was prepared according to the procedure of Donohoe. 3 6,7-Dimethoxyquinoline (S9) The title compound was prepared from 3,4-dimethoxybenzaldehyde according a modified procedure of the one reported by Knochel. 4 3,4-Dimethoxybenzaldehyde (4.15 g, 25 mmol) and aminoacetaldehyde dimethylacetal (4.1 mL, 37.5 mmol) were heated at reflux in toluene (75 mL) using Dean-Stark apparatus. After the appropriate volume of water (ca. 4.5 mL) was collected in the Dean-Stark apparatus (approximately 4 hours) the reaction was cooled to room temperature and concentrated in vacuo. Note: the imine appeared to be unstable on TLC, and as such this reaction cannot be monitored by TLC. The material was dissolved in CH2Cl2 and dried (MgSO4), filtered, and concentrated in vacuo to give imine which was carried on without further purification. Imine (assume 25 mmol) was dissolved in EtOH (25 mL) and sodium borohydride (1.9 g, 50 mmol) was added portionwise. After 1 hour, TLC analysis indicated complete conversion and the reaction was concentrated in vacuo. The crude material was dissolved in H2O (50 mL) and CH2Cl (50 mL) and separated. The aqueous layer was further extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo to give pure amine (4.45 g, 70% over 2 steps) as a colourless oil.
The amine (4.45 g, 17.5 mmol) was dissolved in CH2Cl2 (50 mL) and pyridine (2.1 mL) and cooled to 0 °C. Tosyl chloride (4.4 g, 22.75 mmol) was added portionwise and the reaction was stirred at room temperature for 14 hours. The reaction was quenched with saturated NaHCO3 solution (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by FCC (10-40% EtOAc in pentane) to give sulfonamide (5.56 g, 78%) as a yellow oil.
The solution was heated at reflux for 5 hours, cooled, and washed with Et2O (100 mL). The aqueous layer was made basic with NaOHaq and extracted with CH2Cl2. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by FCC (0-4% MeOH in CH2Cl2) to give isoquinoline S9 (1.63 g, 86%) as a yellow oil which solidified on standing (ca. 1 hour). For each step, the spectroscopic data matched those previously reported by Knochel. 4 5-Morpholinoisoquinoline (S10) The title compound was prepared from 5bromoisoquinoline according to the procedure of Novartis. 5 8-Morpholinoisoquinoline (S11) To a three-necked flask fitted with a condenser was added 8-bromoisoquinoline (2.08 g, 10 mmol), cesium carbonate (6.5 g, 20 mmol), rac-BINAP (311 mg, 5 mol%), morpholine (1.75 mL, 20 mmol), and toluene 80 mL. The solution was sparged with argon for 10 minutes before palladium acetate (110 mg, 5 mol%) was added and the solution heated at reflux for 14 hours. The solution as cooled to room temperature and diluted with 100 mL EtOAc and 100 mL water. The biphasic solution was separated, and the aqueous layer was further extracted with EtOAc (2 x 50 mL).

Synthesis of isoquinolinium iodides
General Procedure C: A mixture of the appropriate isoquinoline (1 equiv.) and aryl halide (1.2 equiv.) in acetone (5 mL per mmol) was stirred in the dark at room temperature for 16 hours. The reaction mixture was filtered under reduced pressure. The resulting solid was washed with ether (50 mL) then dried under vacuum for 10 minutes to give the N-Ar-isoquinolinium iodide salts as solids.
General Procedure D: A mixture of the appropriate isoquinoline (1 equiv.) and methyl iodide (2 equiv.) in CH2Cl2 (2.5 mL per mmol) was heated at 40 °C for 16 hours. The reaction mixture was filtered under reduced pressure. The resulting solid was washed with ether (50 mL) then dried under vacuum for 10 minutes to give the N-methyl-isoquinolinium iodide salts as solids.
General Procedure E: A mixture of the appropriate isoquinoline (1 equiv.) and alkyl iodide (2 equiv.) in 1,4-dioxane (2.5 mL per mmol) was heated at 90 °C for 16 hours. The reaction mixture was filtered under reduced pressure. The resulting solid was washed with ether (50 mL) then dried under vacuum for 10 minutes to give the N-alkyl-isoquinolinium iodide salts as solids.

N-Butyl
x 3). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude compound was purified using chromatography to obtain the pure product.

Palladium Scavenging Experiments
Two substrates were treated with Biotage ISOLUTE SI-TMT scavenging resin, particularly effective at removing trace quantities of palladium, rhodium, ruthenium, nickel, and platinum. Following treatment, these compounds showed no change of reactivity 4-Butylisoquinoline S1 (200 mg) was dissolved in THF (20 mL) and Biotage ISOLUTE Si-TMT scavenging resin (40 mg, 20% w/w) was added and the solution was stirred at room temperature for 3 h. The solution was filtered and concentrated in vacuo to return "purified" S1. This material was reacted with benzyl iodide (0.2 mL) to form salt 1a which was subjected to the standard reaction conditions and gave 2a in 65% (16 hours) and 49% (6 hours) indicating no loss of reactivity.
N-Methyl-4-butylisoquinolinium iodide 1g (400 mg) was dissolved in MeOH (20 mL) and Biotage ISOLUTE Si-TMT scavenging resin (80 mg, 20% w/w) was added and the solution was stirred at room temperature for 3 h. The solution was filtered and concentrated in vacuo to return "purified" 1g. This material was subjected to the standard reaction conditions and gave 2g in 70% (16 hours) indicating no loss of reactivity.
ICP-MS analysis of salt 1a and 1g before and after treatment with Pd-scavenging resins determined that in all cases the Pd-contamination was less than 5 ppm (the detection limit of the machine).

Inductively Coupled Plasma Mass Spectrometry of KOMe (ICP-MS)
Sample Preparation: To a solution of potassium methoxide (2 g) in MeOH, was added HCl (2-3 equiv., 2M in Et2O). The reaction was stirred for 10 minutes then concentrated in vacuo to furnish potassium chloride. Potassium chloride (1 g) was dissolved in 18 megohm water (10 ml), 1 mL of this solution was further diluted in 18 megohm water (10 mL).
The ICP-MS was undertaken by Phil Holdship (Department of Earth Science, University of Oxford).
The potassium methoxide sample (purchased from Sigma Aldrich) gave the following trace metal quantities: Platinum Metals: Ru (0 ppm The following metals were tested for and found not to be present: Co, Ge, Nb, As, Y, La, Sm, Gd, Tb, Ho, Tm, Yb, Lu, U, W, Re. d 4 -MeOH and CH3OD were purchased from Sigma Aldrich and Cambridge Isotope Laboratories respectively and used without further purification. d 2 -Paraformaldehyde was purchased from Sigma Aldrich and used without further purification.
All reactions were performed following General Procedure F, using deuterated reagents where specified in the reaction scheme.

Scheme S1: Tandem methylation-hydroxymethylation reaction
To further understand the tandem methylation-hydroxymethylation process, the standard reaction but using paraformaldehyde-d 2 instead was undertaken (Reaction 1, Scheme S1) and d-2o was isolated with deuterium incorporation in the C1 (0.96D), one proton at the C3 (0.6D), the CH2OH (2.0D), and the methyl (1.9D) positions. Similarly, when using CH3OD in place of MeOH (Reaction 2, Scheme S1) deuterium incorporation was observed in the C1 (0.86D), benzylic (1.50D), C3 (0.3D) and methyl (0.9D) positions. In line with these results, we propose the following mechanism for tandem process (Scheme S1): Reduction of 1 and the trapping of formaldehyde, in the same manner as Scheme 5 in the manuscript, leads to the formation of intermediate 6. At this point, elimination of -OH leads to exocyclic alkene 8 which can undergo an isomerization to form N-benzyl-4-methylisoquinolinum iodide 1 which then participates in the identical mechanism explained in Scheme 5 in the manuscript to furnish the methylated-hydroxymethylated product 2o. This mechanism is consistent with our deuterium studies, particularly the presence of ≈1 proton in the methyl group when paraformalhyded 2 is used and ≈1 deuterium in the methyl group when CH3OD is used.