Synthesis of Tetrahydroisoquinolines Through an Iron-Catalyzed Cascade: Tandem Alcohol Substitution and Hydroamination

Abstract

Rapid assembly of saturated nitrogen heterocyclesthe synthetically more challenging variants of their aromatic relativescan expedite the synthesis of biologically relevant molecules. Starting from a benzylic alcohol tethered to an unactivated alkene, an iron-catalyzed tandem alcohol substitution and hydroamination provides access to tetrahydroisoquinolines in a single synthetic step. Using a mild iron-based catalyst, the combination of these operations forms two carbon–nitrogen bonds and provides a unique annulation strategy to access this valuable core.

Earth-Abundant 3d Transition Metal Catalysts for Hydroalkoxylation and Hydroamination of Unactivated Alkenes

“…No hydroamination product was observed with other electron-deficient protecting groups on the amine due to stronger binding to the cationic metal. This catalytic system was applied to a cascade process for the synthesis of tetrahydroisoquinolines [61]. The tetraphenyl-substituted cyclopentadienone iron(0) tricarbonyl complex was also efficiently used as a precatalyst for the endo-cyclohydroamidation of N-Cbz protected amines tethered to monoallenes (Figure 4, bottom) [53].…”

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…In addition they have also developed an alternate source for nucleophile by replacing acetylene with nitromethane (116) or diethylphosphite (48) to obtain the corresponding 1,2-dihydroisoquinoline in good yields (Scheme 63). As a whole, they were successful in developing an environmentally friendly, operation- ally easy method for the synthesis of 1,2-dihydroisoquinoline.…”

“…[115] Marcyk and Cook reported an iron-catalyzed synthesis of tetrahydroisoquinolines 182 from a benzylic alcohol tethered to an inactivated alkene 180 and sulfonamide 181 (Scheme 96). [116]…”

“…The optimized reaction conditions were employed on wide range of ortho-alkynylaldimines 221 with EDG and EWG on alkyne chain as well as on amine ring to obtain good yields (Scheme 127). [35a] Additionally, authors have expanded the scope of the reaction conditions with different pronucleophiles like MeNO 2 (116) or MeCN (224 a) to access isoquinoline derivatives. However, under the palladium catalyzed reaction conditions these were not acting as a good nucleophiles and hence they gave a moderate yields of around 40% (Scheme 128).…”

Rhodium(II)-Catalyzed Denitrogenative Annulation for the Synthesis of Substituted Tetrahydroisoquinolines

“…16 Recently, the iron-mediated synthesis of THIQs by the allenylation of substituted propagyl alcohols (Figure 1j) 17 and an annulation approach by the tandem alcohol substitution and hydroamination employing a sulfonamide nucleophile was reported (Figure 1k). 18 Noteworthily, transition-metal catalysis or photocatalysis presents a powerful potential in THIQ preparation; however, two or more condensable functional groups are usually necessary to construct the second ring and bring specific functional substitution. 19−22 To address this issue, the need for effective metal catalysis in the transformation of the monosubstituted starting material to the desired THIQ is emerging.…”