Synthesis of 4,4′-Disubstituted and Spiro-tetrahydroquinolines via Photochemical Cyclization of Acrylanilides and the First Synthesis of (±)-trans-Vabicaserin

Abstract

The synthesis of vabicaserin analogues bearing a quaternary center or spiro substitution at the 4-position has been studied via a [6π]-acrylanilide cyclization employing flow photochemistry in a mesoscale and microfluidic flow photoreactor. The method is also used to synthesize 4,4′-disubstituted tetrahydroquinolines and, furthermore, enables the first synthesis of (±)-trans-vabicaserin.

Progress in the Chemistry of Tetrahydroquinolines

“…Koolman and co-workers showed that, when an acetone solution of the acrylanilide derivative 276 was subjected to a photochemical [6π]-cyclization by treatment with quartz-glassfiltered UV light from a mercury middle-pressure lamp in a mesoscale tube-based flow reactor, the fused dihydroquinolinones 277 were obtained in good yields (Scheme 66). 163 These compounds were further reduced with borane−THF and treated with trifluoroacetic acid to remove the Boc protection to furnish (±)-trans-vabicaserin and related 4,4′-disubstituted tetrahydroquinolines 278 in excellent yields. The photochemical step was shown to tolerate well the presence of substituents on the aromatic ring, as well as on the acrylic moiety.…”

“…Koolman and co-workers performed a direct synthesis of spirocyclic substituted 4,4′-cyclobutyl tetrahydroquinolines 289 in a microfluidic flow photoreactor via a [6π] cyclization of an acrylanilide precursor 288 (Scheme 72). 163 A regio-and diastereoselective synthesis of bridged benzothiaoxazepine-1,1-dioxides containing an embedded tetrahydroquinoline unit was achieved in three steps from readily available starting materials (Scheme 73). 170 The starting N-aryl-2-fluorobenzenesulfonamides were alkylated with trans-2,3-epoxycinnamyl alcohol-derived tosylates in the presence of K 2 CO 3 in DMF at 60 °C to give the N-alkyl sulfonamides 290, which underwent an intramolecular epoxide ring-opening in the presence of p-toluenesulfonic acid in toluene at 80 °C to form trans-4-aryl-3-hydroxytetrahydroquinoline derivatives 291.…”

Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry

“…Photochemical cyclizations are historical transformations that are once again gaining utility due to improved reactivity in flow. For instance, at AbbVie a photochemical cyclization was carried out on gram scale, providing a key intermediate 65 for a 5HT 2C program (Scheme A) . Similarly, tricyclic scaffolds have been prepared by [2 + 2] photocycloaddition using a continuous flow setup .…”

“…This endoperoxide 63 was prepared by the introduction of dihydroartemisinic acid 64, oxygen gas, and photosensitizer to 40A). 90 Similarly, tricyclic scaffolds have been prepared by [2 + 2] photocycloaddition using a continuous flow setup. 91 Small scale runs were transitioned to a large-scale flow photoreactor, where 10−20 g of starting material could be processed in a 9.5− 14.6 h period, with isolated yields similar to the small scale runs (Scheme 40B).…”

Light on the Horizon: Current Research and Future Perspectives in Flow Photochemistry

“…Koolman and co-workers carried out the synthesis of vabicaserin analogues by photocyclization reaction using a mesoscale and microfluidic flow photoreactor. 59 Vabicaserin is a polycyclic system with a 1,2,3,4-tetrahydroquinoline core, which has been clinically investigated as a 5-HT 2C agonist for the treatment of schizophrenia. 60 Furthermore, 1,2,3,4tetrahydroquinoline is the substructure of many biologically active compounds and natural products as a consequence.…”