Synthesis of 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines via Pummerer-type cyclization of N -(arylmethyl)- N -methyl-2-aryl-2- (phenylsulfinyl) acetamides

The synthesis of 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines (16) was achieved via the intramolecular cyclization of N -(arylmethyl)- N -methyl-2-aryl-2-(phenylsulfinyl)acetamides (10) utilizing the Pummerer reaction as key step. Trifuoroacetic anhydride induced cyclization of the sulfoxides 10 at ambient temperature readily provided 4-aryl-2-methyl-4-(phenylsulfanyl)- 1,2,3,4-tetrahydroisoquinolin-3-ones (11) in almost quantitative yield. Subsequent reductive removal of the phenylsulfanyl group from 11 with NaBH 4 -NiCl 2 followed by the reduction of the lactam function of the resulting 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-ones (15) furnished the title products 16 in excellent yields. This conversion offers a total synthesis of (±)- cherylline 16g, an amaryllidaceae alkaloid


Introduction
It is well known that the in situ formed thionium ion generated under acidic conditions from an α-sulfinylacyl precursor (Pummerer reaction) is a particularly powerful electrophilic group reacting efficiently with nucleophilic carbon species such as alkenes, aromatics and enol ethers.This reaction was successfully applied for the synthesis of various carbocycles and heterocycles. 1shibashi et al. widely explored the reaction and used it as the key strategy for the synthesis of nitrogen heterocycles such as oxyindoles, 2 3-oxo-1,2,3,4-tetrahydroisoquinolines, 3 1,3,4,5tetrahydro-2H-3-benzazepin-2-one, 4 and for the synthesis of alkaloids such as erythrinan 5

Results and Discussion
The N-(arylmethyl)-N-methyl-2-aryl-2-(phenylsulfinyl)acetamides (10a−d) were prepared as follows (Scheme 2).Treatment of 2-bromophenylacetic acid (3) with potassium benzenethiolate in eyhanol under reflux provided 2-(phenylsulfanyl)acetic acid (4).The acid chloride prepared from 4 was condensed with the amines 2a−c giving rise to the corresponding amides 9a−c.The preparation of (±)-2-(4-benzyloxyphenyl)-2-(phenylsulfanyl)acetic acid (8) started from (±)-2-(4-hydroxyphenyl)-2-hydroxyacetic acid (5) (Scheme 2).Alkylation of 5 with benzyl chloride in the presence of potassium carbonate and tetraethylammonium bromide (TEAB) in refluxing acetone gave benzyl (±)-2-(4-benzyloxyphenyl)-2-hydroxyacetate (6).Bromination of 6 with phosphorus tribromide in dry diethyl ether yielded benzyl (±)-2-(4-benzyloxyphenyl)-2bromoacetate (7).Treatment of 7 with potassium benzenethiolate in dioxane under reflux afforded 8; the corresponding acid chloride was condensed with the amine 2c and afforded the amide 9d.The 1 H NMR spectra of 9a−d indicated a mixture of E/Z isomers with respect to the rotational isomerism of the amide group.Oxidation of the sulfides 9a−d with sodium metaperiodate in aqueous methanol or acetone afforded a diastereomeric mixture of sulfoxides 10a−d, respectively.When a solution of the sulfoxide 10b in benzene was treated with TFAA at room temperature for 10 min, the expected cyclization was readily induced, and 6,7-dimethoxy-2-methyl-4-phenyl-4-(phenylsulfanyl)-1,2,3,4-tetrahydoisoquinolin-3-one (11b) was formed (Scheme 3).Cyclization of 10c also occurred under similar conditions and furnished 11c.00cking the alkoxy groups enhancing the nucleophilicity of the phenyl ring of the Nbenzylacetamide moiety, and on treatment with TFAA in benzene at room temperature the tetrahydoisoquinolin-3-one 11a was obtained in only 20% yield together with non-cyclized products 12 and 13.Addition of BF3•Et2O 9 to a benzene solution of 10a containing TFAA considerably improved the cyclization reaction and increased the yield of 11a at the expense of the side products 12 and 13.On the contrary, the sulfoxide 10d bearing a benzyloxy group in two benzene rings, when treated with TFAA in benzene at room temperature rapidly decomposed to give a complex mixture, and no products could be isolated from this reaction mixture.Previously, we noticed that this Pummerer-type cyclization in some cases 9a was strongly dependent on the solvent used.Therefore, we carried out the reaction in several solvents and found that tetrahydrofuran (THF) dramatically improved the cyclization reaction.Thus, reaction of 10d with TFAA in THF induced the expected cyclization at room temperature leading to its completion within 10 min and furnishing 11d.Similarly, the reaction of 10c in THF afforded 11c, although the cyclization in this solvent was slower (300 min) compared with the reaction carried out in benzene as described above.These results demonstrate that the cyclization of 10 readily proceeds under mild conditions.The putative reaction intermediate, the sulfonium ion 14, features the C=S bond in conjugation with the 2-aryl group.This is considered to favor the formation of the electrophilic intermediate 14, and, in turn, facilitates the intramolecular cyclization reaction.We achieved the conversion of the 4-aryl-

Scheme 4
Reduction of 11d with LAH yielded two products, dibenzyl cherylline 16d and dibenzyl 4phenylthiocherylline 17.On the other hand, treatment of 11d with aluminum hydride selectively reduced the lactam carbonyl group and produced 17.Reductive desulfurization of 17 with NaBH4−NiCl2 afforded 16d, together with the partially debenzylated product 16f.Dibenzyl cherylline 16d was resistant to debenzylation under hydrogenolytic conditions.For example, hydrogenation of 16d over 10% Pd−C in MeOH failed, while hydrogenation over PtO2 in acetic acid selectively caused debenzylation of the 7-benzyloxy group to afford 4'-O-benzyl cherylline 16f.Hydrolysis of either 16d or 16f with conc.HCl furnished (±)-cherylline 16g in good yields.In summary, the synthesis of (±)-cherylline 16g starting from the amine 2c was achieved in five steps with a total yield of about 35%.In conclusion, we present a convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines using the Pummerer reaction as a key step.The acid-induced intramolecular cyclization under C−Cbond formation between the α-C of 2-aryl-2-(phenylsulfinyl)acetamides and the ortho-C of the attached N-arylmethyl group effectively proceeded under extremely mild conditions.This

ISSN 1551-7004
Page 170  ARKAT USA, Inc method is applicable for the construction of 4-aryl-1,2,3,4-tetrahydroisoquinoline ring systems 10 bearing an acid labile group such as the benzyloxy substituent, and it offers a useful alternative synthesis of (±)-cherylline 16g in addition to the many previously reported ones.The organic extract from each reaction mixture was washed with brine, dried over anhydrous Na2SO4 or MgSO4 before concentration in vacuo.N-Arylmethyl-N-methylamines 2a−c were prepared according to the known method by condensation of arylaldehydes 1a−c with methylamine followed by reduction with NaBH4.

General experimental procedure
To a solution of 15 (1 molar eq) in dry THF (30−100 mL) was added under ice-cooling LiAlH4(1 molar eq), and the mixture was refluxed for 1−2 h.Et2O saturated with water was added to the reaction mixture, and insoluble material was filtered off.The product was chromatographed to give 16.In the case of 15g the starting material (52%) was recovered, and the product 16g was characterized as the diacetate 16h (12%).