Alternative synthesis of (+/-) Cherylline dimethyl ether

An alternative synthesis of isoquinoline alkaloid (+/-) cherylline dimethyl ether is reported. The steps involved are acid-catalyzed Michael addition of veratrole to p -methoxycinnamic acid, Curtius rearrangement, reduction of isocyanate intermediate followed by Pictet-Spangler cyclization.


Introduction
Cherylline 1 and latifine 2 are the two 4-aryltetrahydroisoquinoline alkaloids isolated from Amaryllidaceae plants. 1 Apart from the natural existence, 4-aryltetrahydroisoquinolines are of interest due to various pharmacological activities. 2 For example, nomifensine 3 3 and dichlofensine 4 4 exhibit central nervous system activity and inhibit serotonin and dopamine uptake mechanisms (Scheme 1).

Scheme 1
There are several reports 5 on the syntheses of (+/-) cherylline and of (+/-) latifine which include some efficient chiral syntheses.Most of the reported methods for the synthesis of (+/-) cherylline are either multistep or low yielding.In continuation of our work 6 in developing efficient methods for the synthesis of alkaloids, we report herein an alternative efficient synthesis of (+/-) cherylline dimethyl ether.

Results and Discussion
Our retrosynthetic analysis of (+/-) cherylline dimethyl ether 5 is depicted in scheme 2. We anticipated that 5 could be constructed from amine 6 via a Pictet-Spangler ring annulation which, in turn, could be obtained by reduction of the corresponding isocyanate.The required isocyanate would arise from the acid 7 via Curtius reaction.Lastly, acid 7 was to be assembled by Michael addition of veratrole to p-methoxycinnamic acid.Scheme 2 Thus, veratrole was subjected to Michael reaction in presence of 75% H 2 SO 4 to obtain 3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)propanoic acid 5n 7 in 40% yield.Use of TFA instead of 75% H 2 SO 4 for alkylation improved the yield to 92%.Modified Curtius reaction 7 using diphenyl phosphorazidate (DPPA) gave low yield of the isocyanate in our hands.Resorting to the more conventional Curtius conditions using ethyl chloroformate gave isocyanate 9 in 93.7% yield.Immediate reduction of the isocyanate 9 by lithium aluminium hydride gave expected amine 6 in 82.1% yield.The crude amine 6, without further purification, on Pictet-Spangler reaction gave (+/-) cherylline dimethyl ether 5 in 67% yield (Scheme 3).The overall yield of the 4-step synthesis was found to be 47.7% from p-methoxycinnamic acid 8, and is better than most of the reported methods.In conclusion, we have devised a very short and efficient method for the synthesis of (+/-) cherylline dimethyl ether.This simple and facile nature of tetrahydroisoquinoline synthesis should allow the construction of a wide variety of interesting and useful analogous molecules.

Experimental Section
General Procedures.Melting points were determined by Thiele's tube apparatus and are uncorrected.IR spectra were recorded on Shimadzu FT-IR, IR Prestige-21 (KBr pellet or neat sample). 1 H NMR and 13 C NMR spectra were recorded on 300 MHz Bruker instruments.The multiplicities of carbon signals were obtained from a distortionless enhancement by polarization transfer (DEPT).Coupling constants (J) are given in Hz and rounded to the nearest 0.1Hz.The TLC plates were developed with ethyl acetate (EA)-hexanes.The silica gel used for column chromatography was Loba Chemie 60-120 mesh size.Nitrogen was used as the inert atmosphere.The glassware was equipped with a rubber septum and reagent transfer was effected by syringe techniques.Tetrahydrofuran (THF) was distilled over lithium aluminium hydride and stored over sodium wire.Acetone was distilled from potassium permanganate before storage over anhydrous potassium carbonate.
Isocyanate 9 (1.86 g, 5.94 mmol) in dry THF (5 mL) was slowly added to the suspension of lithium aluminium hydride (LAH) (1.2 g, 29.5 mmol) in THF (10 mL) under inert atmosphere.After refluxing for 18.0 h, the reaction mixture was cooled to 5 o C and chilled water was slowly added to it.The aluminium hydroxide formed was filtered over celite and washed with boiling chloroform.The filtrate also was extracted with boiling chloroform (6 X 15 mL).All the organic extracts and washings were combined, dried over Na 2 SO 4 , filtered and concentrated to obtain 1.56 g (82.1 %) of crude 6 which was pure enough (TLC).IR (film, cm -1 ) 3124 (NH).