An efficient route to N-alkylated 3,4-dihydroisoquinolinones with substituents at the 3-position

A facile synthetic procedure for the production of N-alkylated 3,4-dihydroisoquinolinone derivatives is described. The desired products were obtained by N-alkylation of 3,3′-dimethyl-3,4-dihydroisoquinoline derivatives followed by oxidation of the resulting iminium salts. Reaction conditions for both steps were very mild and the desired cyclization products could be obtained in good yield. This strategy allows the generation of N-substituted 3,4-dihydroisoquinolinone derivatives with substituents at the 3-position.


Introduction
3,4-Dihydroisoquinolinone 1 is an important member of the class containing a core structure found in compounds that exhibit biological and pharmacological properties, such as antinausea/vomiting, 1 antidiabetic, 2,3 and antiallergy/antiasthmatic 4 activities. Some examples of pharmacologically active compounds that include the dihydroisoquinolinone moiety are shown in Fig. 1. Its suitable size and moderate polarity as a pharmacophore make 3,4-dihydroisoquinolinone a suitable scaffold that has been widely used in various drug candidates. For 3,4-dihydroisoquinolinone derivatives, the introduction of substituents at the 3-position generally improve their biostability 5 because the substituent prevents oxidation of the unsubstituted 3-position. Nevertheless, only a few methods for effective preparation of N-alkylated 3,4-dihydroisoquinolinone with substituents at the 3-position are available, most of which are related to the synthesis of N-methyl analogues. 6 One of the simplest synthetic methods of the N-alkylated dihydroisoquinolinone skeleton is direct N-alkylation of Nunsubstituted dihydroisoquinolinone A (Scheme 1). 7 The Nalkylation reaction, however, oen does not proceed in the case of substrates with some substituents at the 3-position. Another method for preparing the skeleton involves benzylic oxidation of N-alkylated tetrahydroisoquinoline B-1. 8 However, this route cannot be applied to substrates in which another position can be easily oxidized. Using this approach, the precursor is easy to synthesize because the nitrogen atom of tetrahydroisoquinolines B-2 is more nucleophilic than that of 3,4-dihydroisoquinolinones A. However, in the case of 3-substituted analogues, precursors B-2 are not obtained via cyclization reactions of the corresponding phenethylamine derivatives B-3. 9 Thus, we have focused on the oxidation reaction of N-alkylated iminium salts C-1. As previous reports are limited to 3unsubstituted analogues, 10 we examined whether this strategy was compatible with 3-substituted dihydroisoquinolinone derivatives. In the course of the reaction, N-alkylation proceeds via a less sterically hindered transition state when compared with that of direct N-alkylation of dihydroisoquinolinone A. Therefore, this method has an apparent advantage for N-alkylation of sterically hindered analogues. In this work, we developed an effective synthetic method of 3-substituted N-alkyldihydroisoquinolinone derivatives via iminium intermediates.

Results and discussion
Preparation of 3,3-dimethyl-dihydroisoquinolinium salt 3,3-Dimethyl-3,4-dihydroisoquinoline 8, was prepared by referring to a previously described procedure (Scheme 2). 11 Our synthesis began with commercially available 2-bromophenylacetic acid 2, which was converted into an ester and reacted with methyl Grignard reagent to afford the tertiary alcohol 4. Nucleophilic substitution of 4 with chloroacetonitrile followed by reaction with thiourea afforded the tertiary amine 6 12 in high yield. Amidation of the tertiary amine 6 with ethyl formate under neat conditions produced the formamide 7 in 85% yield. Tandem cyclization of 7 using oxalyl chloride followed by iron(III) chloride afforded a tricyclic intermediate, which was pyrolyzed by MeOH-H 2 SO 4 to give 3,3-dimethyl-3,4dihydroisoquinoline in 89% yield.
Aer obtaining 3,3-dimethyl-3,4-dihydroisoquinoline 8, we examined the formation of isoquinolinium key precursors 9. For the preparation of the 3,3-dimethyl-dihydroisoquinolinium salt 9 (Scheme 3), dihydroisoquinoline 8 was reacted with methyl bromoacetate (2 equiv.) in acetonitrile at 60 C. Aer 6 h, the desired product 9 was produced and precipitated as a colorless powder. The obtained powder was sufficiently pure for use in the next reaction without further purication.

Synthesis of 3-substituted dihydroisoquinolinones
We next examined the oxidation of the 3,4-dihydroisoquinolinium salt 9. The reaction was rst examined in the presence of hydrochloric acid and dimethyl sulfoxide with reference to a previously described procedure (Table 1, entry 1), 10a but the desired product was not obtained. Next, we focused on optimizing the oxidation conditions. When 9 was reacted with m-chloroperoxybenzoic acid, dealkylation of 9 to dihydroisoquinoline 8 occurred predominantly (entry 2). Employing Dess-Martin periodinane as the oxidant, the reaction became messy and a complex product mixture that included 8 was obtained (entry 3). When oxone was employed as the oxidant, no reaction was observed (entry 4). However, when 9 was reacted with oxone in the presence of sodium bicarbonate, desired product 10 was obtained as the major product (entry 5). This suggested that basic conditions were preferable for 3-substituted dihydroisoquinolinones. As the yield was not satisfactory, further experiments were conducted. Treatment of 9 with potassium ferricyanide in the presence of potassium hydroxide gave the desired product as the hydrolyzed carboxylic acid 11 in 69% yield (entry 6). 13 Dealkylated compound 8 was also obtained as a minor product.
We also examined the oxidation reaction of isoquinolinium salts, including those with other alkyl substituents on the nitrogen atom. 14 As expected, under optimal conditions, the desired dihydroisoquinolinones were obtained in high yields (Scheme 4). However, when dihydroisoquinolinium salt 16 was employed in the oxidation reaction, the desired product was obtained only in trace amounts, while dealkylated compound 8 was generated as the major product (Scheme 5). This was probably due to steric hindrance at the oxidation site.

Investigation of the reaction mechanism
We hypothesize that the mechanism of the reaction involves a hydroxide ion as an oxygen source and proceeds through a radical pathway, because hexacyanoferrate(III) is a typical oneelectron oxidizing agent. 15 To verify this hypothesis, we conducted the oxidation reaction of isoquinolinium salt 12 under a nitrogen atmosphere. As a result, the reaction proceeded smoothly and the desired product 13 was obtained in excellent yield (Scheme 6, eqn (1)), suggesting that atmospheric oxygen (O 2 ) was not the oxygen source. Next, we investigated the reaction of 12 with only potassium hydroxide solution to conrm that hydroxide ions were the oxygen source. The tetrahydroisoquinolinol intermediate 18 was determined by LC/MS and 1 H NMR analysis 16 of the crude mixture. Furthermore, when potassium ferricyanide was added to the solution of intermediate 18, generation of the desired product was detected (eqn (2)). When the reaction was conducted in the presence of a radical scavenger, the reaction mixture became messy and the desired product was not detected (eqn (3)). Based on these experimental results, we concluded that the oxidation reaction proceeded through a radical process via the tetrahydroisoquinolinol intermediate 18. Oxone (

Conflicts of interest
There are no conicts to declare.