Reaction of 1-Alkylthioisoquinolinium Salts with Active Methylene Compounds.

Abstract

We have previously reported on the reaction of 2-methylthioquinolinium salts with active methylene compounds for the formation of a carbon-carbon bond.1) Additionally, various methods for the synthesis of indolizine derivatives have been reported.2) In view of the recent report by Iwao and Kuraishi.2) on the novel total synthesis of the marine alkaloid lamellarins, which contain the pyrrolo[2,1-a]isoquinoline skeleton (Chart 1), 3) functionalized pyrrolo-[2,1-a]isoquinolines would function as very useful synthetic intermediates toward their syntheses. The conventional methods for preparing the substituted pyrrolo[2,1-a]isoquinoline derivatives are either via Michael condensation of Reissert compounds, 4) or via 1,3-and 1,5-dipolar cycloaddition reactions. 5,6) In this paper, we report a novel method for the synthesis of a pyrrolo[2,1-a]isoquinoline skeleton using the cyclization of 2-benzyl-1-(substituted methylene) isoquinolines, which are readily prepared by the reaction of 2-benzyl-1-alkylthioisoquinolinium iodides with active methylene compounds.Reaction of 1-Alkylthioisoquinolinium Iodides with Active Methylene Compounds Initially, the reaction of active methylene compounds with isoquinolinium salts that have a methylthio group as a leaving group at the 1-position was examined under mild conditions in the presence of sodium hydride (Chart 2, Table 1). 2-Methyl-and 2-benzyl-1(2H)-thioisoquinolones (3, 7) 4) were prepared from 2-methyl-and 2-benzyl-1(2H)-isoquinolones (1, 8) 2) in excellent yields, respectively. The reaction of thioisoquinolones (3, 4) with methyl iodide (5a) afforded 2-methyl-and 2-benzyl-1-methylthioisoquinolinium iodides (6a, 9) 7) in 99 and 77% yields, respectively. The reactions of 6a with straight-chain active methylene compounds (8a-c) in the presence of sodium hydride for 1.5 h at room temperature afforded 2-methyl-1-(substituted methylene)isoquinolines (9a, 88%; 9b, 81%; 9c, 85%, respectively) in high yields. However, reactions of 6a with straight-chain active methylene compounds (8d-f) afforded 9d-f in moderate yields. Reactions of 6a with cyclic active methylene compounds (8g, h) at 90°C for 3 h gave 2-methyl-1-(substituted methylene)isoquinolines (9g, h) in 92% and 61% yields, respectively. Similarly, the reaction of 7 with 8a-e produced 2-benzyl-1-(substituted methylene)-isoquinolines (10a, 95%; 10b, 98%; 10c, 99%; 10d, 88%; 10e, 53%, respectively). To examine the effects of the alkylthio group at the 1-position, the experiments were repeated using other alkyl iodides. In comparison to methyl iodide, the reaction of 3 with ethyl iodide (5b) and isopropyl iodide (5c) afforded low yields of the corresponding 1-alkylthioisoquinolinium salts (6b, 75%; 6c, 52%). Furthermore, the reactions of 6b, c with 8a and with 8g gave products [9a ( 65%, 65%); 9g (42%, 40%)] in lower yields than that of 6a with 8a, g ( Table 1). These results can be explained by assuming that the enol form arising from the active methylenes (8d-f) would be more stable than the corresponding keto form, and would te...

Six‐Membered Heterocycles: Quinoline and Isoquinoline

“…Classical reactions of isoquinolin-1-ones are N-and O-alkylation. Deprotonation of 123 with base and reaction of the resulting bidentate anion with alkyl halides or tosylates are reported to result in alkylation exclusively at nitrogen to give products like 348 (Scheme 17.168) [465], although traces of the corresponding O-alkylated products are also obtained [466]. Harder electrophiles, such as triflic anhydride and silylating agents, react at the exocyclic oxygen, although the nucleophile may be the neutral molecule in these cases [467,468].…”

Heterocycles with a bridging nitrogen atom. 19. Development of routes for the synthesis of oxazoloisoquinolinium salts based on phenacylation of α-methyl-1(3)-isoquinolones

“…It is known that the alkaline salts of 1-isoquinolone 6a may be subject to selective N-alkylation by various alkylating agents [11][12][13], including phenacyl bromide [14]. The N-phenacylation of 1-methoxyisoquinoline 7a in low yield (~8%) has been described [10].…”

Synthesis of Pyrrolo[2,1-a]isoquinolines by a Tandem 1,5-Electrocyclisation-Oxidation Process

“…4 Since the discovery of the potent cytotoxic and topoisomerase I inhibitory activity of lamellarines, a number of new synthetic strategies have been developed, based on, for example, intramolecular oxidative biaryl coupling, 5 1,3-dipolar cycloaddition of azomethine ylides, 6 thermal reactions of 4ixovazoline derivatives (obtained by cycloadditions of 3,4-dihydroisoquinoline N-oxides with alkynes), 7 in-tramolecular Heck reactions 8 and cyclisation of 1-or 2benzylisoquinolines. 9,10 Our own interest in the development of new protocols for the synthesis of nitrogen-containing heterocycles by 1,5or 1,7-electrocyclisation of azomethine ylides, 11 prompted us to investigate the feasibility of a tandem electrocyclisation-oxidation process for the synthesis of pyrrolo[2,1-a]isoquinolines using our recent observations on the reactivity of various stabilised a,b:g,d-unsaturated azomethine ylides generated, by the deprotonation method, from isoquinolinium salts. 12 We report here a practical and general method for the synthesis of 1,2-diaryl-5,6-dihydropyrrolo[2, 1-a]isoquinolines.…”