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

Abstract

SummaryNucleophilic trapping of iminium salts generated via oxidative functionalisation of tertiary amines is well established with stabilised carbon nucleophiles. The few reports of organometallic additions have limited scope of substrate and organometallic nucleophile. We report a novel, one-pot methodology that functionalises N-substituted tetrahydroisoquinolines by visible light-assisted photooxidation, followed by trapping of the resultant iminium ions with organometallic nucleophiles. This affords 1,2-disubstituted tetrahydroisoquinolines in moderate to excellent yields.

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

“…The organic layer was evaporated under vacuum and the crude mixture was purified on silica gel column chromatography using DCM/MeOH (9/1) as an eluent to afford methopholine (72.0 mg, 0.208 mmol, 98%) as a slightly yellow solid. Data are consistent with those reported in the literature . 1 H NMR (300 MHz, CDCl 3 ) δ 7.25 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 6.55 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.43 (t, J = 5.4 Hz, 1H), 3.23–3.08 (m, 1H), 2.84–2.65 (m, 4H), 2.55–2.51 (m, 1H), 2.49 (s, 3H), 2.12–1.97 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 147.4, 147.3, 141.4, 131.3, 129.8, 129.6, 128.4, 126.8, 111.3, 109.9, 62.6, 56.0, 55.8, 48.2, 42.7, 36.8, 30.9, 25.5; LC/MS m / z 346.8 [M + H + ].…”

“…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.…”

“…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 …”

Copper-catalyzed asymmetric sp3 C–H arylation of tetrahydroisoquinoline mediated by a visible light photoredox catalyst

“…During the last decade, numerous examples of sp 3 C–H bond arylation procedures have been developed [1,21–29]. In 2008, our group developed the first direct sp 3 C–H arylation of THIQ with arylboronic acids using a copper catalyst (Scheme 1) [30].…”