Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129–168) On the nature of the intermediate in the Lewis acid-promoted synthesis of dihydroisoquinolines from nitriles and -phenylethyl chloride Electron A. Mistryukov* and Olga N. Sorokina N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax:+7 095 135 5328 In addition to Lewis acidity, the ability to co-ordinate both reactants is a prerequisite for catalyst activity in the cyclisation reaction of b-phenylethyl chloride and alkyl- or aryl nitriles to dihydroisoquinolines.The known cyclisation reaction of b-phenylethyl chloride to dihydroisoquinolines with nitriles and SnCl4 presents a useful synthetic method.1 In this communication we present our efforts to elucidate the connection between the structure of the nitrile component and the nature of the Lewis acid.Based on the experimental evidence, an attempt is made to rationalize some mechanistic aspects of the reaction, namely, the nature of the intermediate. Two variants of the experimental conditions were used to obtain the results presented below.† (A) Low-boiling acetonitrile was used as excess reactant and solvent and (B) the solvent was phosphorus oxychloride for high-boiling nitriles.As shown in preliminary experiments, the literature procedure for 1 ® 3 conversion is more convenient when run in the solvent POCl3 (Scheme 1). Apart from the ease of end product separation this solvent significantly activates the Lewis acid and may be recovered for repeated use.The results are presented in Table 1. So, the acidity of Lewis catalysts is not directly related to the yield of cyclized products. To explain why some moderately strong acids are active and give cyclic products (entries 1, 2 and 5), but some do not (entries 3, 4, 6) — including the strongest of the acids tested AlCl3 — it is helpful also to consider the specific structure of the ‘reactive’ (entries 1 and 2) and ‘unreactive’ (entries 3 and 4) nitriles.To the same end, also informative are the mechanistic considerations of another synthetic approach to dihydroisoquinolines via b-phenylethylamines (Bishler–Napiralski procedure, Scheme 1, 1 ® 4 ® 3 and 6 ® 5 ® 4 ® 3).2 Obviously, it may be assumed that both synthetic pathways have the same intermediate, nitrilium cation 4, which originates either by dechlorination of imidoyl chloride or alkylation of alkyl nitrile on nitrogen.But this assumption is an oversimplification of the actual process. In fact, in this line of reasoning the best catalyst for conversion of 1 and 2 to nitrylium 4 should be the strongest Lewis acid AlCl3, which, if it bound chlorine to complex anion AlCl4 and thus facilitated the formation of carbonium ion intercepted by nitrile, would immediately give the cyclized product.† Method A. To 20 ml of acetonitrile was added SnCl4 (0.04 mol) gradually with cooling followed by chloride 10 (0.04 mol). After heating at 60–70 °C for 6 h and overnight at room temperature, the reaction mixture was decomposed by water with cooling (40 ml).Pentane was added (40 ml) and then, with cooling, the aqueous layer was saturated with solid KOH. The organic extract (after drying over KOH, filtration through Al2O3 and evaporation) was converted into chloride by the action of 5 ml of trimethyl chlorosilane in 5 ml BuiOH and 10 ml ethyl acetate. After filtration and washing with 10×2 ml of EtOAc the recovered yield was 6.67 g (79%) of 11 as the hydrochloride,2 mp 176– 177 °C. 1H NMR (D2O) d: 1.58 (s, 6H, gem Me), 2.90 (s, 3H, Me), 3.28 (s, 2H, CH2), 7.55–8.13 (m, 4H, aromatic). Method B. To a mixture of 1.16 mol b-phenylethyl chloride (163.5 g, 150 ml) and 1.16 mol acetonitrile (47.6 g, 61 ml) was added 1.16 mol of POCl3 (177.5 g, 105 ml) and, gradually with cooling, 1.16 mol (303.2 g, 133 ml) SnCl4.After gentle reflux for 5 h and overnight at room temperature, 300 ml of ethyl acetate was added. The complex salt was filtered off and washed with 500 ml of the same solvent and 100 ml of diethyl ether. Yield was 465.4 g (95%); to a suspension of this complex in 800 ml of water was added, with cooling, 800 ml of 10 M sodium hydroxide. The base after extraction with diethyl ether and drying over solid NaOH was distilled, bp 100–105 °C/5 mmHg, yield 104.6 g (62%).Chloride mp 198–200 °C. 1H NMR (base, CDCl3) d: 2.23 (s, 3H, Me), 2.47 (t, 2H, Ar–CH2), 3.50 (t, 2H, N–CH2), 7.14 (m, 4H, aromatic); 13C NMR (CDCl3) d: 19.19 (t, Me), 24.87 (t, Ar–CH2), 40.78 (t, N–CH2), 128.57 (q, Ar–C), 136.76 (t, C=N). b Cl N H R + RCN SnCl4 SnCl5 1 2 3 1 + 2 – Cl– (MCln) N C R N Cl– – Cl– (MCln) C(Cl)R 4 5 NHCOR 6 Cl 7 SnCl4 RCN CN O Me SnCl4 8 Cl 9 Me 10 NCR SnCl4 Cl Me N HCl·SnCl4 Me 11 Me Me SnCl4 MeCN a R = Me b R = CH2Ph c R = CH2Cl d R = CH2CH2OMe Scheme 1 ax is the anion in the complex salt.bNo organic basic fraction was isolated after aqueous work-up. cExtensive chlorination of the end product and intermolecular condensation of the starting chloride are the main side reactions.Table 1 The yield of isoquinoline as a function of nitrile structure and Lewis acid. Entry Nitrile Lewis acid Productsa Yield (%) 1 2a SnCl4 3a x = SnCl5 85 2 2b SnCl4 3b x = SnCl5 80 3 2c SnCl4 — 0b 4 2d SnCl4 — 0b 5 2a TiCl4 3a x = TiCl4 + n 60 6 2a ZnCl2 — 0b 7 2a SbCl5 3a x = SbCl6 60c 8 2a AlCl3 — 0bMendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129-168) In reality, this catalyst is completely inactive and the starting chloride 1 may be recovered almost quantitatively after standard work-up. At the same time, AlCl3 smoothly converts amide 6a into isoquinoline 3a, presumably via 4. Thus, it is not only the Lewis acidity of the catalyst which is of importance, but also some other intrinsic property of the metal chlorides used for 1 ® 3 conversion.We believe that this crucial factor is the metal coordination number and the ease of ligand exchange in the transition complex. A logical assumption is that all components of the reaction, i.e., nitrile and chloride, are incorporated into the inner sphere of the metal (7, Scheme 1). Within such a framework, the aluminium chloride complex with nitrile is unable to add another ligand, b-phenyethyl chloride, or to exchange it for one of the chlorides.Also, following the same line of reasoning, the unreactivity of nitrile 2d may be explained by coordination as in 8 or 9. Nitrile 2c is inactive (see entry 3) also by virtue of this ‘wrong’ coordination (on chlorine) or not coordinating at all (reduced nucleophilicity of nitrogen). Interestingly, if the two important parts of the isoquinoline molecule are assembled together as in 4, aluminium chloride and all the other chlorides in Table 1 are effective as cyclisation catalysts. References 1 M. Lora-Tamayo, R. Madronerob and G. G. Munoz, Chem. Ber., 1960, 93, 289. 2 V. C. Schclyaev, B. B. Alexandrov, M. I. Vihrin and G. I. Lagotkina, Khim. Geterotsikl. Soedin., 1987, 806 (in Russian). Received: Moscow, 27th March 1998 Cambridge, 11th May 1998; Com. 8/02403K