One‐Pot α‐Amidosulfone‐Mediated Variation of the Pictet–Spengler Tetrahydroisoquinoline Synthesis, Suitable for Amide‐Type Substrates

Abstract

The development of Pictet–Spengler reactions from amide substrates is a challenging problem. We report here that the reaction between amide‐type compounds (including carbamates, amides, ureas and diketopiperazines), aldehydes and p‐toluenesulfinic acid constitutes an efficient method for the preparation of tetrahydroisoquinolines or pyrazino[2,1‐b]isoquinolines. Unlike previously known methods, this one‐pot Pictet–Spengler protocol avoids the need for strong Lewis or Brønsted acid catalysts.

Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents

“…While we acknowledged that the fastest approach to our planned symmetrical urea derivatives would involve the use of double Pictet−Spengler reactions from the known 92 urea derivative 16, this method had the disadvantage that amide-type compounds are challenging Pictet−Spengler substrates; indeed, ureas have rarely been studied in this regard and usually only for the case of very reactive aldehydes such as formaldehyde. 93 We found, nevertheless, that our recently developed method based on the generation of α-amidosulfone intermediates 94 provided a general solution to our problem, allowing the preparation of compounds 10 and 11 via a pseudo three-component reaction between 16 and two molecules of aliphatic or aromatic aldehydes, in refluxing toluene containing one equivalent of toluenesulfinic acid. Under these conditions, the reaction was fully diastereoselective and afforded exclusively the trans isomers 10, confirming our previous findings 94 (Scheme 1 and Table 1).…”

“…93 We found, nevertheless, that our recently developed method based on the generation of α-amidosulfone intermediates 94 provided a general solution to our problem, allowing the preparation of compounds 10 and 11 via a pseudo three-component reaction between 16 and two molecules of aliphatic or aromatic aldehydes, in refluxing toluene containing one equivalent of toluenesulfinic acid. Under these conditions, the reaction was fully diastereoselective and afforded exclusively the trans isomers 10, confirming our previous findings 94 (Scheme 1 and Table 1).…”

“…The known compounds 18−24 (Figure 3) were prepared by treatment of the urea derivative 16 with a variety of aldehydes in the presence of toluenesulfinic acid in refluxing dichloromethane 94 in order to extend the structure−activity relationship study to nonsymmetrical, monocyclic urea derivatives. Compound 25, which was isolated during the preparation of 19 and arose from the alkylation of the latter compound by the toluenesulfinic acid−propanal adduct, 94 belongs to the same family of monocyclic ureas and was also studied biologically. To further probe the role of molecular symmetry in TRPM8 inhibition, we also prepared the known N-acetyl compound 26, 95 which can be viewed as a "half" of compounds 10 and 11.…”

“…Method A: α-Amidosulfone Variation of the Pictet−Spengler Reaction. To a solution of 1,3-bis(3,4dimethoxyphenethyl)urea 16 92,94 (1.0 equiv) in toluene (5 mL) was added the suitable aryl or alkyl aldehyde (3 equiv) and p-toluenesulfinic acid (1.1−3.0 equiv), and the solution was heated at 120 °C for 12 h. The mixture was poured onto a saturated solution of NaHCO 3 (5 mL), which was extracted with DCM (2 × 30 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by flash column chromatography using mixtures of petroleum ether: diethyl ether to give compounds 10a−m and 11j.…”

“…13 The related 18−20 and 22−25 are known compounds. 94 General Procedure to Obtain 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolines 27−30. To a solution of compound 16 (1.0 equiv) in AcOH or toluene (5.0 mL) was added the suitable aldehyde (3 equiv) and the suitable catalyst (1.8−3.0 equiv), and the reaction mixture was heated at 80−120 °C for 12 h. The mixture was quenched with a saturated solution of NaHCO 3 (10 mL), which was extracted with DCM (2 × 30 mL).…”