C1‐Substituted N‐Alkyl Tetrahydroisoquinoline Derivatives through V‐Catalyzed Oxidative Coupling

Abstract

In the THIQ of it:N-Alkyl tetrahydroisoquinolines are oxidatively coupled with a variety of nucleophiles in the presence of m-CPBA and [VO(acac)₂]. This method has been applied to the synthesis of the opioid methopholine

One-pot functionalisation of N-substituted tetrahydroisoquinolines by photooxidation and tunable organometallic trapping of iminium intermediates

“…Photoactivation of 16a and trapping of the resultant benzylic endo -iminium salt with 18 resulted in a 56% yield of 3 . To our knowledge, this concise synthesis of 3 is higher yielding (based on THIQ 16a ) than previously reported syntheses [ 13 , 46 – 47 ] with no intermediate isolations required.…”

“…Encouraged by these results, we decided to apply our methodology to THIQ 16a using Grignard 18 in a synthesis of methopholine ( 3 , Scheme 2 ). Previous syntheses of 3 involving oxidative functionalisation of 16a have used (4-chlorophenyl)acetylene as a pronucleophile [ 13 , 46 ]. However, isolation and hydrogenation of the resulting THIQ intermediate are required to access 3 .…”

“…Alternatively, the α-amino radicals can be trapped by electrophiles [ 7 – 9 ]. Oxidative C–H functionalisation of THIQs is reported using Cu(I) [ 10 – 11 ], Fe(III) [ 12 ], V(IV) [ 13 ] and I 2 [ 14 – 15 ] catalysts, but also with heterogeneous [ 16 ], metal-organic [ 17 – 18 ] and organic [ 19 – 20 ] photocatalysts. Such catalysts are used in combination with various stoichiometric oxidants including oxygen [ 16 , 21 ].…”

Metal‐Free Multicomponent Construction of Tetrahydroisoquinoline‐Indole Derivatives via In Situ Generated ortho‐Quinonoid Intermediate

“…Not surprisingly, significant efforts have been put forward for the synthesis of C(1)‐indolylated THIQs. The most frequently used approach include the cross dehydrogenative coupling (CDC) of C(1)‐H bond of THIQ with indole in the presence of metal catalyst and oxidant [13] such as CuBr/TBHP, [13a] Fe(NO 3 ) 3 /TBHP, [13b,c] VO(acac) 2 / m ‐CPBA, [13d] V 2 O 5 /O 2 , [13e] Meso‐MnOx‐550, [13f] NaAuCl 4 /TBHP [13g] etc . (Scheme 1a).…”

Succinct Syntheses of Methopholine, (±)‐Homolaudanosine, and (±)‐Dysoxyline via Metal‐free One‐Pot Double Alkylation on 1‐Methyl‐3,4‐dihydroisoquinolines

“…For instance, solifenacin is an approved drug as a selective muscarinic M3 receptor antagonist for the treatment of overactive bladder (Figure ) . Methopholine is an opioid analgesic more effective than codeine . Homolaudanosine and dysoxyline, structurally very similar to methopholine, were isolated from Dysoxylum lenticellare showing molluscicidal activities …”