Bischler−Napieralski Cyclization−N/C-Alkylation Sequences for the Construction of Isoquinoline Alkaloids. Synthesis of Protoberberines and Benzo[c]phenanthridines via C-2‘-Functionalized 3-Arylisoquinolines¹

Abstract

Efficient synthetic routes to isoquinoline alkaloids of the protoberberine and benzo[c]phenanthridine classes are reported. The key transformations are derived from the intramolecular cyclization of C-2'-functionalized N-(1,2-diarylethyl)amides or enamides via 3-arylisoquinoline derivatives. Thus, under Bischler-Napieralski reaction conditions (PCl(5), nitrile as solvent, room temperature) N-(1,2-diarylethyl)amides 12 regioselectively yielded 2,3-disubstituted 13,14-dihydroprotoberberinium salts 20, a scarcely studied oxidation state in this class of alkaloids. Subsequent reduction of the iminium bond gave the known coralydine (21a) and O-methylcorytenchirine (21b) and their 8-phenyl analogue 21c. The one-pot preparation of these dihydroprotoberberinium salts 20 is shown to proceed with cleavage of the silyl ether and immediate halogenation of the resulting hydroxyl group, followed by cyclization of the obtained N-(1,2-diarylethyl)amide 18 to a 3,4-dihydroisoquinoline derivative 19 and subsequent intramolecular in situ N-alkylation of the latter imine. Ready access to planar 8,9-dialkoxylated benzo[c]phenanthridinium salts is also described. Condensation of ketoester 23 with benzylamine in the presence of titanium(IV) chloride, followed by acetylation, afforded a mixture of naphthylamide 24 and (E)-enamide 25. Both enamides were efficiently cyclized by POCl(3). While the planar benzo[c]phenanthridinium salt 26 was directly produced from 24, the (E)-enamide 25 gave the 3-arylisoquinolinium salt 27, which was reduced and intramolecularly C-alkylated to yield the tetracyclic nucleus of these alkaloids.

Application of ortho-acylated phenylacetic acid esters to the synthesis of 1-substituted isochromanes

“…Compounds 3a,d,f,j,l were previously characterized. 46 2-(2-(2,4-dichlorobenzoyl)-4,5-dimethoxyphenyl)acetate (3i). 25 (t, 3H, J=7.2), 3.71 (s, 3H), 3.95 (s, 3H), 3.96 (s, 2H), 4.15 (q, 2H, J=7.1 …”

An Efficient Synthesis of 3‐Substituted Isoquinoline and Pyridine Derivatives by Gold Catalyzed Intramolecular Cyclization from o‐Alkynyloximes

“…Accordingly, a number of synthetic methods for isoquinolines have been developed; for example, classic methods, such as the Pomeranz–Fritsch , Bischler–Napieralski , and Pictet–Spengler reactions, have considerable drawbacks such as the use of strong acids and elevated temperatures. In Bischler–Napieralski and Pictet–Spengler reactions, an additional step involving dehydrogenation is required to complete the synthesis of isoquinoline.…”

Regio‐ and Stereoselective Stevens Rearrangement of Benzyltetrahydroprotoberberinium Salts

“…The imminium annelation of C2Ј-functionalized 3-arylisoquinolines (disconnection c) has proved to be efficient for the synthesis of 8-substituted tetrahydroprotoberberine based on a double cyclization approach. [15] Finally, disconnection d, based on the introduction of the C-8 substituent, has also been applied once the isoquinoline skeleton is formed. In this last case, protoberberinium salts [16] or 8-oxoprotoberberine alkaloids, [17] easily available through classical methods, are treated with organometallic reagents to yield the corresponding 8-substituted berbines.…”