Reactivity of 3-Ethoxycarbonyl Isoquinolinium Salts Towards Various Nucleophilic Reagents: Applications to the Synthesis of New 1,2-Dihydroisoquinoline-3-carboxylates

Different types of novel 1,2-disubstituted 1,2-dihydro isoquinolines were synthesized by addition reactions of organolithium, alcoholates and borohydride reagents with various isoquinolinium salts. The leaving group character of the isoquinoline moiety was also evidenced.


Introduction
In a recent paper [1] we have reported that the reaction of lipophilic 3-ethoxy-carbonyl-N-alkylisoquinolinium perfluorobutanesulfonate with Grignard reagents provides a very pratical entry to stable 1,2-disubstituted 1,2-dihydroisoquinoline-3-carboxylates (DIC) [2]. The 1,2-dihydroisoquinoline-3-carboxylic acid derivatives are usually considered to be very air-sensitive species and are rather difficult to purify [3]. In an attempt to overcome the limitations of the standard methods [4], we have now found that the presence of an electron-attracting carboxyl function adjacent to the imino bond increases the stability of N-alkyl isoquinolinium salts. Therefore, the 1,2-addition of various nucleophilic reagents to iminium C=N double bond is a valuable approach for the synthesis of DIC derivatives. We now describe the extension of this methodology for the preparation of new 1,2-disubstituted 1,2-dihydroisoquinolines. Preparative procedures and NMR ( 1 H-, 13 C-) structure of the starting materials are also reported here.
Salt 5b was easily obtained by anion metathesis of isoquinolinium bromide 5a with commercially available potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate [9] (Scheme 2). The choice of the lipophilic perfluorobutanesulfonate as counteranion was guided by the fact that this allowed a simple analysis of the isoquinolinium core by 1 H-NMR spectroscopy and this counteranion was also less nucleophile than the starting bromide [4a] and should provide salt 5b with better solubility in organic solvents, particularly in THF. Salt 5b was readily prepared by simple stirring of salt 5a with potassium perfluorobutanesulfonate (1.5 eq.) in dry refluxing ethanol. After removal of the solvent in vacuo, a crystalline precipitate was obtained in ether at room temperature. With salt 5b in hand, we studied the reactivity of this lipophilic isoquinolinium salt towards n-butyl lithium reagent [10] (Scheme 3). The dropwise addition at 0°C of a commercial solution of n-butyl lithium (1.6M in hexane, 3.2 eq.) to a solution of 5b in dry THF led, after 12 hours at room temperature, to a in 56% yield of the expected 5-(1-butyl-2-benzyl-1,2-dihydroisoquinolin-3-yl)nonan-5-ol (7a), which was stable in air and also after purification by chromatography on silica gel. The structure of the racemic mixture 7 was substantiated by its 1 H-, 13 C-NMR and HRMS analysis. The specific rotation of the crude reaction mixture was however disappointingly low ([α] D +1.2 (0.5 M, EtOH)). We have also examined the addition reaction of sodium methoxide [11] with salt 5b (Scheme 4). Reaction of 5b with MeONa (1.1 eq.) in dry methanol at room temperature for 6 hours gave directly the methyl 1-methoxy-1,2-dihydroisoquinoline-3-carboxylate (8) in 80% yield. This one-pot reaction involves: (a) a regioselective addition of the nucleophilic reagent on the iminium moiety (C-1) of 5b associated to (b) a transesterification reaction catalyzed by MeONa. The 1,2-dihydroisoquinoline 8 was fairly stable in solution under an inert atmosphere, but all attempts to isolate it resulted in significant decomposition. However it was possible to analyse it by 1 H-, 13   In a similar fashion, we have also studied the addition of MeONa to salt 5c using the same reaction conditions (Scheme 4). Attempts to produce the cyclized 1,2-dihydroisoquinoline-3-carboxylate 10 which can be considered a N,O-acetal, by intramolecular addition reaction were unsuccessful [12]. Salt 5c was found to produce 5-methoxy-7,8-dihydro-[5H,6H]-9-oxa-[5a]-aza-cyclohepta-[b]-naphtalene-10-one (11) in 86% yield via the intermediates 9c and 5d' which could not be isolated. We tried to follow this domino reaction by 1 H-NMR and thus could observe the formation of 11 and the disappearance of the signal of the ethyl ester group (C-3) of salt 5c. The mechanism for the domino synthesis involves: (a) the deprotonation of the OH group on the N-propyl side chain by MeONa to give in situ the zwitterionic intermediate 9c followed by (b) lactonization [13] to produce 5d', which undergoes (c) a regioselective addition reaction of MeONa on the iminium moiety (C-1). As expected, the domino reaction lead to a racemic mixture of 11. The final step of this mechanism was confirmed by the regioselective addition of MeONa to salt 5d (X = Br) which gave the desired compound 11 in quantitative yield. The isolated N,O-acetal 11 proved to be quite stable in air and flash chromatography afforded in a pure product.
Next we have evaluated the reduction of the functionalized quaternary isoquinolinium salts 5e,f derived from ethyl isoquinolin-3-carboxylates 4a,b (Scheme 2). Reduction of salts 5 (5e, R 1 = MeO; 5f, R 1 = H) proceeded easily with a slight excess of NaBH 4 in ethanol at 25°C. The reaction took place in good yield, as monitored by TLC. The corresponding dihydro compounds 6e,f were moderately stable in solution under an inert atmosphere. After purification of 6e,f by flash chromatography with methylene chloride as eluent (6e, R f = 0.6; 6f, R f = 0.4), the isolated ethyl 2-ethoxycarbonylmethyl 1,2-dihydroisoquinolin-3-carboxylates 6e,f decomposed rapidly in air [14]. Therefore it was possible to analyze them only by 1 H-NMR. After a few days at room temperature, the 1 H-NMR of products 6e,f showed a mixture of 6 together with AcOEt, the starting isoquinoline 4 and side-products which were also detected by TLC. The formation of isoquinoline 4 during the decomposition of the dihydro compound 6 demonstrated the leaving group character of the isoquinoline moiety [15].
In order to demonstrate the presence of isoquinoline 4 in this case, we decided to study the reactivity of salts 5e,f towards triphenylphosphine in refluxing methylene chloride (Scheme 5). After 6 hours, the analysis of the crude reaction mixture by 1 H-NMR showed the presence of isoquinoline 4 together with the phosphonium salt 12. There is no doubt that this reaction consisted in the transfer of the N-alkyl group between the salt 5 and triphenylphosphine by a nucleophilic substitution. In this reaction, the formation of the salt 12 is in agreement with the leaving character of the isoquinoline moiety.

Acknowledgements
Much of the work described in this paper was supported by Merck Eurolab, Div. Prolabo (F). We also thank Professor Jack Hamelin for fruitful discussions.

General
Thin-layer chromatography (TLC) was accomplished on 0.2-mm precoated plates of silica gel 60 F-254 (Merck). Visualization was made with ultraviolet light (254 and 365 nm) or with a fluorescence indicator. For preparative column chromatography, silica gel 60F 254 Merck (230-240 Mesh ASTM) was used. Melting points were determined on a Kofler melting point apparatus and are uncorrected. The specific rotation [α] D were mesured with a PERKIN ELMER 141 polarimeter. 1 H-NMR spectra were recorded on a BRUKER AC 300 P (300 MHz) spectrometer, 13 C-NMR spectra on a BRUKER AC 300 P (75 MHz) spectrometer. Unless stated otherwise the solvent used was CDCl 3 , chemical shifts are expressed in parts per million downfield from tetramethylsilane used as an internal standard and δ values refer to singlet absorptions. Data are given in the following order: δ value, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad), number of protons, coupling constants J are given in Hertz. The mass spectra (HRMS) were taken on a VARIAN MAT 311 at a ionizing potential of 70 eV in the Centre Régional de Mesures Physiques de l'Ouest (CRMPO, Rennes). Absolute ethanol was distilled over magnesium after standing overnight and stored over molecular sieves (3Å). Solvents were evaporated with a Buchi rotary evaporator. All reagents were purchased from Acros, Aldrich, Avocado and Strem and were used without purification.