C-1 Alkynylation of N-Methyltetrahydroisoquinolines through CDC: A Direct Access to Phenethylisoquinoline Alkaloids

Abstract

Direct cross-coupling between N-methyltetrahydroisoquinolines and alkynes using CuI-DEAD is presented. It affords the regioselective C-1-alkynylated products in good yield. This regioselectivity is in contrast to the results reported earlier in the reaction of N,N-dimethylbenzyl amine where the N-methyl alkynylated product was formed exclusively or predominantly. The C-1-substituted propargylic isoquinolines were easily reduced to phenethylisoquinolines with Pd/C. This reaction sequence provides a short route to synthesize methopholine, homolaudanosine and other phenethylisoquinoline alkaloids.

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

“…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 .…”

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

“…All of three natural products were obtained in good yields. Compared with the literature precedents, [19][20][21][22][23][24][25][26][27][28] our synthetic approach for these natural products is unique and concise, requiring only two steps from DHIQ 1d.…”

“…17,18 Methopholine is an opioid analgesic more effective than codeine. [19][20][21][22] Homolaudanosine [23][24][25] and dysoxyline, [26][27][28] structurally very similar to methopholine, were isolated from Dysoxylum lenticellare showing molluscicidal activities. 29 3,4-Dihydroisoquinoline (DHIQ) is a well-known precursor for the syntheses of diverse THIQs.…”

Regioselective Direct C‐Alkenylation of Indoles

“…Deep eutectic solvents are featured by several advantages over ionic liquids since they are biodegradable, non‐toxic and cost effective and can be used for the reaction of different β‐diketones and β‐ketoacid derivatives with indoles . Finally, molecular iodine is also an active catalyst for the same process, although formation of 3‐indolyl enones is limited to the utilization of 2‐substituted indoles because of the concomitant formation of bisindoles using unsubstituted substrates …”

“…[184] Finally,m olecular iodine is also an active catalyst for the same process, although formation of 3-indolyl enones is limited to the utilization of 2-substituted indoles because of the concomitant formation of bisindoles using unsubstituted substrates. [185]…”