Intramolecular cyclisation of arylalkyl isothiocyanates. Part I. Synthesis of 1-substituted 3,4-dihydroisoquinolines

Abstract

With triethyloxonium tetrafluoroborate or ethyl or methyl fluorosulphonate, 2-arylethyl isothiocyanates cyclised to give a 1 -ethylthio-or 1 -methylthio-3,4-dihydroisoquinoline, respectively. These compounds were prepared also by successive cyclisation of the isothiocyanates with aluminium chloride or polyphosphoric acid and alkylation of the resultant 3,4-dihydroisoquinoline-? (2H) -thione. They are useful starting materials for the synthesis of other 1 -substituted 3,4-dihydroisoquinolines, e.g. 1 -amino-compounds.?At approximately the time our first patent application 2 was published another appeared in which compounds (12), ( 14), and the hydroiodide of compound (1 7) are described along with several l-amino-3,4-dihydroisoquinolines [C.

Demethylative Lactonization Provides a Shortcut to High-Yielding Syntheses of Lamellarins

“…Although ours are not the shortest syntheses of lamellarins on record, the overall yields are outstanding and are, in fact, higher than any hitherto reported in the literature for any lamellarin, let alone those we have chosen as examples (cf 82% for lamellarin G trimethyl ether, compared with a previously reported highest yield of 69%). In addition, no other lamellarin synthesis reported in the periodicals literature to date has yielded gram quantities of the target products.…”

“…Our synthesis of the trimethyl ethers of lamellarins G ( 6 ) and D ( 7 ) as well as lamellarins A4 ( 3 ) and H ( 5 ) began with three cheap, readily available precursors: homoveratrylamine ( 14 ), homoveratric acid ( 15 ), and 1,2,4-trimethoxybenzene ( 16 ) (Scheme ). Thiolactam 12 needed for the Eschenmoser sulfide contraction was obtained in two telescoped steps from homoveratrylamine ( 14 ) by adaptation of a reported method, entailing formation of an intermediate isothiocyanate 17 by treatment of 14 with carbon disulfide and ethyl chloroformate, followed by cyclization with polyphosphoric acid at 80–90 °C. Trituration of the crude product with methanol afforded spectroscopically pure dihydroisoquinolinethione 12 in 92% yield.…”

“…Stirring was continued for 30 min, after which the product was filtered through a glass sinter and washed with additional water. The crude solid product was then triturated under boiling methanol (250 mL); after cooling, it was was filtered and dried to provide the pure product 6,7-dimethoxy-3,4-dihydroisoquinoline-1­(2 H )-thione ( 12 ) (17.0 g, 76.1 mmol, 92%); pale yellow powder, mp 231–232 °C (lit., 223 °C). 1 H NMR (300 MHz, CDCl 3 , δ): 8.08 (s, 1H), 8.03 (br s, 1H, NH), 6.61 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.55 (td, J = 7.0, 3.4 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H).…”

“…This has the advantage of avoiding the need for additional protection and deprotection steps for the incipient phenol because a simple readily available anisole serves as the precursor. • Although ours are not the shortest syntheses of lamellarins on record, the overall yields are outstanding and are, in fact, higher than any hitherto reported in the literature for any lamellarin, 3 let alone those we have chosen as examples (cf 82% for lamellarin G trimethyl ether, compared with a previously reported highest yield of 69% 20 ). In addition, no other lamellarin synthesis reported in the periodicals literature to date has yielded gram quantities of the target products.…”

“…1 H NMR (500 MHz, CDCl 3 , δ): 7.44 (s, 1H), 7.11 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.45 (s, 1H), 3.94 (s, 3H), 3.91 (s, 6H), 3.87 (s, 6H). 13 (20). 6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-thione (12) (5.98 g, 26.8 mmol) was added to a solution of the bromoketone 19 (12.0 g, 28.2 mmol, 1.05 equiv) in dry MeCN (150 mL), and the resulting solution was stirred at room temperature for 18 h to ensure complete salt formation, after which time Ph 3 P (7.03 g, 26.8 mmol, 1 equiv) was added.…”