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Org. Synth. 1958, 38, 58
DOI: 10.15227/orgsyn.038.0058
1-METHYLISOQUINOLINE
[Isoquinoline, 1-methyl-]
Submitted by J. Weinstock and V. Boekelheide1.
Checked by N. J. Leonard, Terry W. Milligan, and William R. Sherman.
1. Procedure
Caution! All the operations should be carried out in a well-ventilated hood because of the toxic nature of hydrogen cyanide and the cyanide solutions.
A. 1-Cyano-2-benzoyl-1,2-dihydroisoquinoline2 (Reissert's compound3) (Note 1). In a 5-l. three-necked flask equipped with a Hershberg stirrer, a dropping funnel, and a condenser is placed a solution of 391 g. (6.0 moles) of potassium cyanide in 2.5 l. of water and 258 g. (2.0 moles) of isoquinoline (freshly distilled from zinc dust). The mixture is maintained below 25° by immersion in an ice bath (Note 2). The stirrer is started, and, when the isoquinoline has formed an emulsion with the aqueous solution, 562 g. (4.0 moles) of benzoyl chloride is added over 3 hours. The stirring is continued another hour or until the Reissert's compound has separated as small, hard, tan spheres. The reaction mixture is cooled further in the ice bath, and the product is collected on a large Büchner funnel. It is washed on the funnel with successive portions of 400 ml. of water, 400 ml. of 3N hydrochloric acid, and 500 ml. of water. The product is then recrystallized from 2–3 l. of commercial absolute ethanol using 2.5 g. of activated carbon to effect partial decolorization of the solution. The hot filtration to remove the carbon is done by means of a heated Büchner funnel. The filtrate is cooled in an ice bath and filtered when cold. Long standing in the presence of the supernatant liquid causes the adsorption of dark material by the product. The cream-colored crystals which separate are collected on a Büchner funnel. washed with 100 ml. of cold 95% ethanol, and dried in air overnight. The yield of dry 1-cyano-2-benzoyl-1,2-dihydroisoquinoline, m.p. 125–127°, sufficiently pure for use in the next step, is 303–400 g. (58–77%).
B. 2-Benzoyl-1-cyano-1-methyl-1,2-dihydroisoquinoline. A 3-l. round-bottomed flask, a 500-ml. dropping funnel, a condenser, and a stirrer are dried in an oven and then arranged so that a nitrogen atmosphere can be maintained in the flask with the use of a mercury bubbler. The apparatus is flushed with dry nitrogen for 1 hour, and 83.5 g. (0.32 mole) of 1-cyano-2-benzoyl-1,2-dihydroisoquinoline, 350 ml. of dry dioxane (Note 3), and 100 ml. of anhydrous ether are added. The stirrer is started, and, when the solid is dissolved completely, the flask is immersed in an ice-salt bath at −10°. Then 450 ml. of a 0.78N ether solution of phenyllithium (0.35 mole) (Note 4) is added dropwise, with stirring, during 30 minutes. The reaction mixture turns a deep red, and as the addition is continued a red solid separates. Ten minutes after the addition is complete 56.2 g. (0.40 mole) of methyl iodide is added, and the reaction mixture is stirred in the cold for 2 hours, then overnight at room temperature. The reaction mixture is transferred to a separatory funnel and washed with three 50-ml. portions of water. The organic solution is filtered, and the solvent is removed under reduced pressure. If the residue does not crystallize immediately upon evaporation of the solvent, crystallization may be induced by scratching the sides of the flask and cooling. The crystals are transferred to a Büchner funnel, washed on the funnel with 50 ml. of cold 95% ethanol, and dried. The yield of dry 2-benzoyl-1-cyano-1-methyl-1,2-dihydroisoquinoline in the form of cream-colored crystals, m.p. 120–122°, is 62–63 g. (71–72%) (Note 5).
C. 1-Methylisoquinoline. In a 500-ml. round-bottomed flask equipped with a reflux condenser are placed 62.2 g. (0.227 mole) of 2-benzoyl-1-cyano-1-methyl-1,2-dihydroisoquinoline, 50 ml. of 95% ethanol, and a solution of 37.6 g. (0.57 mole) of 85% potassium hydroxide in 100 ml. of water. The mixture is heated under reflux for 1.5 hours, during which time the solid dissolves and the solution becomes homogeneous. After the solution has cooled, it is extracted with four 75-ml. portions of ether. The combined ethereal extracts are washed with two 25-ml. portions of water and dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration and of the solvent by concentration under vacuum, the residue is distilled under reduced pressure to give 24–26 g. (74–80%) of colorless 1-methylisoquinoline, b.p.81°/1 mm.; nD25 1.6102, nD20 1.6119 (Note 6).
2. Notes
1. This is essentially the procedure of Padbury and Lindwall.2
2. If the mixture is not kept cold during the addition of the benzoyl chloride, the product is likely to be highly colored.
3. The dioxane is dried as described by Fieser.4 It is kept in a glass-stoppered bottle sealed with wax. The ether is commercial anhydrous ether dried over sodium wire.
4. A convenient preparation of phenyllithium is described by Wittig.5 The ethereal solution may be titrated by adding an aliquot to water and titrating to the methyl orange end point with standardized hydrochloric acid.
5. Another 10 g. (11%) of impure 2-benzoyl-1-cyano-1-methyl-1,2-dihydroisoquinoline may be obtained by adding water to the cold mother liquor until it becomes turbid. The mixture is heated until the turbidity disappears, and the resulting solution is cooled slowly, then refrigerated. The additional product obtained by this method is contaminated with Reissert's compound and should not be used in the next step if pure 1-methylisoquinoline is desired.
6. This method may be used to prepare other 1-substituted isoquinolines. The submitters have prepared 1-benzylisoquinoline and 1-butylisoquinoline by this method.6
3. Discussion
1-Methylisoquinoline has been prepared by the catalytic dehydrogenation of 1-methyl-3,4-dihydroisoquinoline prepared by the Bischler-Napieralski reaction, which involves treating β-phenylethylacetamide with a strong dehydrating reagent at elevated temperatures.7,8,9,10,11,12 1-Methyl-3,4-dihydroisoquinoline has been prepared from β-phenylethylacetamide by using polyphosphoric acid, and the same reagent produced some 1-methylisoquinoline from N-acetyl-dl-phenylalanine.13 1-Methylisoquinoline has also been prepared from β-phenyl-β-hydroxyethylacetamide by using phosphorus pentoxide,14 and by cyclization of the Schiff base obtained from acetophenone and aminoacetal15 or from α-phenylethylamine and glyoxalsemiacetal.16
This preparation is referenced from:

References and Notes
  1. University of Rochester, Rochester, New York.
  2. Padbury and Lindwall, J. Am. Chem. Soc., 67, 1268 (1945.)
  3. Reissert, Ber., 38, 3427 (1905).
  4. Fieser, Experiments in Organic Chemistry, 3rd ed., p. 284, D. C. Heath and Co., Boston, 1955.
  5. Wittig, Newer Methods of Preparative Organic Chemistry, p. 576, Interscience Publishers, Inc., New York, 1948; Org. Syntheses Coll. Vol. 3, 757 (1955).
  6. Boekelheide and Weinstock, J. Am. Chem. Soc., 74, 660 (1952).
  7. Whaley and Hartung, J. Org. Chem., 14, 650 (1949).
  8. Leonard and Boyer, J. Am. Chem. Soc., 72, 2980 (1950).
  9. Späth, Berger, and Kuntara, Ber., 63B, 134 (1930).
  10. Barrows and Lindwall, J. Am. Chem. Soc., 64, 2430 (1942).
  11. Dey and Ramanathan, Proc. Natl. Inst. Sci. India, 9A, 193 (1943).
  12. Pictet and Kay, Ber., 42, 1973 (1909); Sugasawa and Tachikawa, Tetrahedron, 4, 205 (1958).
  13. Snyder and Werber, J. Am. Chem. Soc., 72, 2962 (1950).
  14. Mills and Smith, J. Chem. Soc., 121, 2724 (1922); Pictet and Gams, Ber., 43, 2384 (1910); Ukita, Nakazawa, and Tamura, Japan. J. Exptl. Med., 21, 259 (1951) [C. A., 47, 12392 (1953)].
  15. Pomeranz, Monatsh., 15, 299 (1894).
  16. Schlittler and Müller, Helv. Chim. Acta, 31, 914 (1948).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

polyphosphoric acid

ethanol (64-17-5)

hydrochloric acid (7647-01-0)

ether (60-29-7)

hydrogen cyanide (74-90-8)

nitrogen (7727-37-9)

potassium cyanide (151-50-8)

Acetophenone (98-86-2)

carbon (7782-42-5)

benzoyl chloride (98-88-4)

potassium hydroxide (1310-58-3)

zinc (7440-66-6)

sodium wire (13966-32-0)

Methyl iodide (74-88-4)

Phenyllithium (591-51-5)

magnesium sulfate (7487-88-9)

dioxane (5703-46-8)

α-Phenylethylamine (3886-69-9)

1-Methylisoquinoline,
Isoquinoline, 1-methyl- (1721-93-3)

isoquinoline (119-65-3)

1-Cyano-2-benzoyl-1,2-dihydroisoquinoline (844-25-7)

2-Benzoyl-1-cyano-1-methyl-1,2-dihydroisoquinoline

1-Benzylisoquinoline (6907-59-1)

1-butylisoquinoline

1-methyl-3,4-dihydroisoquinoline

β-phenylethylacetamide (877-95-2)

β-phenyl-β-hydroxyethylacetamide

glyoxalsemiacetal

phosphorus pentoxide (1314-56-3)

methyl orange (547-58-0)

N-acetyl-dl-phenylalanine