Methylisoquinoline

Checked by N. J. Leonard, Terry W. Milligan, and William R. Sherman. 

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. 

l-Cyano-2-benzoyl-l,2-dihydroisoquinolinei (Reissert s compound3) (Note 1). In a 5-1. three-necked flask equipped with a Hershberg stirrer, a dropping funnel, and a condenser is placed a 

2-Benzoyl-l-cyano-l-methyl-l,2-dihydroisoquinoline. A 3-1. 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 l-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 0.78 N ether solution of phenyllithium (0.35 mole) (Note 4) is added drop-wise, 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 

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-l-cyano-l-methyl-l,2-dihydroisoquinoline, 50 ml. of 95% ethanol, and a solution of 32.0 g. (0.57 mole) of 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 °/l mm. 1.6102, w2D° 1.6119 (Note 6). 

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Amination of isoquiaoline with sodamide ia aeutral solveats gives 1-aminoisoquinoline [1532-84-9]. This product is coaverted to 1-hydroxyisoquiaoliae [491-30-5] by diazotizatioa and hydrolysis. Either this compound or 3-methylisoquinoline [1125-80-0] can be obtained ia exceUeat yields by the same modified Chichibabia reactioa described for 2-hydroxyquiaoiiae (121). 

Alkyl Isoquinolines. Coal tar contains small amounts of l-methylisoquinoline [1721-93-3] 3-methylisoquinoline [1125-80-0] and 1,3-dimetliylisoquinoline [1721-94-4J. The 1- and 3-methyl groups are more reactive than others in the isoquinoline nucleus and readily oxidize with selenium dioxide to form the corresponding isoquinoline aldehydes (174). These compounds can also be obtained by the hydrolysis of the dihalomethyl group. The 1- and 3-methyhsoquinolines condense with benzaldehyde in the presence of zinc chloride or acetic anhydride to produce 1- and 3-styryhsoquinolines. Radicals formed by decarboxylation of carboxyUc acids react to produce 1-aIkyhsoquinolines. 

A mixture of 2-chloro-A-(2-hydroxyl-l-methyl-2-phenylethyl)benzamide (44) (9.5g, 24.9 mmol) and P2O5 in o-chlorobenzene (1,50 mL) was refluxed overnight. Upon completion, the reaction was cooled to room temperature and then chilled to 0 °C. To the crude reaction mixture, 300 mL of water was cautiously added. The resulting dark solution was washed with toluene (2 x 50 mL). The aqueous layer was cooled to 0 °C and 50% NaOH added to final pH of 11. The resulting mixture was extracted with toluene (4 x 50 mL). The toluene fractions were combined, dried, filtered and concentrated in vacuo. The residue was crystallized from benzene to afford l-(2-chlorophenyl)-3-methylisoquinoline (45) as a white solid (6.68g, 80%). M.P. = 107-108 °C H NMR (CDCI3) S 8.45 (s, IH), 8.11 (d, IH), 7.85 (dt, IH), 7.41-7.68 (bm, 6H), 2.51 (s, 3H). 

The complete degradation of isoquinoline has not been reported, which indicates that this molecule is not as susceptible to degradation as quinoline. Aislabie et al. [336] found that using an Acinetobacter strain, the degradation of isoquinoline was accompanied by the accumulation of 1-hydroxyisoquinoline. This strain did not metabolize 1,5-dihydroxyisoquinoline nor 1-methylisoquinoline. So, its inability for full degradation was explained in terms of steric hindrance. The enrichment technique leads to a metabolic improvement but results in complete degradation. 

Hydroxy-3-methylisocarbostyril has been prepared by the present method,4 and in 12-15% yield by the ozonization of 3-methylisoquinoline-2-oxide.6... 

Methylisopropylbenzene. See Cymene Methyl isopropyl ketone (MIPK), 14 584 in MEK-MIPK-water system, 22 304-305, 306, 307 Methylisoquinolines, 21 205 Methylisothiazolinone, antimicrobial used in cosmetics, 7 831t... 

How could you synthesize l-methylisoquinoline from ben-zaldehyde and suitable reagents via a multi-step approach ... 

The Reissert-Henze and the Feely-Beavers-Tani reactions are considered together in this section because of their similarity. The former involves cyanation of acyloxy (formed in situ) (Scheme 113), and the latter alkoxy (Scheme 114), quaternary salts. The Reissert-Henze reaction is a facile, fairly general reaction for quinoline and isoquinoline AT-oxides (Table 19) with cyanation occurring a to the ring nitrogen. Certain substituents inhibit reaction, for example a 1-methyl group (equation 125), and others undergo replacement (Scheme 130) (81H(15)98l). Reaction of 1-methylisoquinoline 2-oxide with benzoyl chloride... 

How ever, deprotonation/alkylation of enantiomerically pure 1-iminomethyl-substituted 1,2,3,4-tetrahydro-1-methylisoquinoline bearing an achiral auxiliary similar to the chiral auxiliary of c led to racemic product only21. Therefore, the lithiated intermediate 8 turned out to be configurationally unstable and stereoselectivity in the alkylation of 4 relies on the higher thermodynamic stability of 5 versus its benzyelic epimer (Model B). 

When the tertiary center in 6 containing the chiral auxiliary is subjected to deprotonation/ benzylation the stereoselective formation of l-benzyl-l,2,3,4-tetrahydro-l-methylisoquinoline (97-98% ee) was reported which interestingly had the R configuration. Hence, the monoalky-lated intermediate related to 8 is alkylated from the bottom face, opposite to that found with unsubstituted 5. Obviously the existence of two diastereomeric lithiocompounds accounts for these results. Now the strong temperature dependence of the selectivity, which usually hints that an equilibrium is involved, can also be easily understood. 

Problem 20.40 Outline a mechanism for the Bischler-Napieralski synthesis of 1-methylisoquinoline from N-acetylphenylcthylamine by reaction with strong acid and P,0, and then oxidation of the dihydroisoquinoline intermediate. 4... 

The dimsyl ion also adds to carbon—carbon double bonds, and if the mixture is heated for several hours, methanesulfenate is eliminated. The overall result is methylation, and for compounds such as quinoline or isoquinoline (eq. 20), yields are nearly quantitative (50). The reaction sequence for isoquinoline to 1-methylisoquinoline is as follows ... 

Fig 7. Cyclic voltammograms in DMF of 3-methylisoquinoline in the absence (a) and presence (b, c, and d) of increasing concentrations of butyl bromide, v = 10 mV sec (Reprinted from Ref. 25 with permission from Elsevier Sequoia S.A.)... 

The radical may attack either the anion-radical or isoquinoline in the latter case, a second electron is transferred from an A7. The reductive rert-butyl-ation of 3-methylisoquinoline gives mainly 162 and 163 together with small amounts of 4-, 5-, or 8-substituted dihydroisoquinolines. Imine 163 was oxidized to 164 during workup40 [Eq. (102)]. 

Benzo[6]thiophene forms continuous solid solutions with molecules of similar molecular geometry (e.g., indene, indole, or isoquinoline), but eutectics with molecules of significantly different geometry (e.g., 3-methylisoquinoline, 2-methyl- and 2,6-dimethylnaphthalene, or dibenzothiophene).197,198 Naphthalene and benzo[6]thiophene form a system of limited solid solutions,54,199 which accounts for the difficulties encountered in their separation (see Section II, B). 

Methylisoquinoline with DMAD in ether gives a cyclobutapyr-roloisoquinoline (cf. 316)375 and yet another type of product (329) which could be formed via a complex scheme with an ester shift.318 375... 

Phenylpropiolic ester with l-hydrazino-3-methylisoquinoline gave... 

The examples selected to illustrate some of the important cyclisation reactions leading to substituted quinolines and isoquinolines are quinoline [(100), X = H], 8-nitroquinoline [(100), X = N02], 8-hydroxyquinoline [(100), X = OH], 2-methylquinoline (101), 2,4,6-trimethylquinoline (102), 2-phenylquinoline-4-carboxylic acid (103) and 6-methylisoquinoline (104). 

Retrosynthetic analysis for 6-methylisoquinoline (104) reveals p-tolu-aldehyde and a-aminoacetaldehyde. 

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