Isoquinolines 4-methylisoquinolines

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. 

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. 

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... 

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 ... 

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). 

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). 

To a stirred solution of 1,2,3,4-tetrahydro 6,7-dimethoxy-l-methyl-isoquinoline (35.2 g, 0.17 m) in methylene chloride (50 ml) under nitrogen at ambient temperature was added p-nitrophenylacetic acid (31.4 g,0.17 m) and then portionwise dicyclohexylcarbodiimide (37.0 g, 0.18 m) and the mixture stirred for 3 hr. The precipitated solid was removed by filtration and the filtrate evaporated to an oily residue. The residue was treated with 500 ml methanol and the solid precipitate collected by filtration to give, after drying, N-(4 nitro-phenylacetyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-methylisoquinoline as a yellow solid, 66.0 g (100% yield). The product contains a small amount of dicyclohexylurea. 

When isoquinoline N-oxide [(160) R = H] or 3-methylisoquinoline A oxide [(160) R=Me] are treated with p-toluenesulfonyl chloride,... 

The isoquinolines 9 were synthesized from acetophenone precursors, quaternary 1-methylisoquinolines, or by the Bischler-Napieralski procedure. 

Ancisirocladus is the only genus of the Ancistrocladaceae and comprises some twenty species of lianas and shrubs found in the tropical rain forest of Asia and Africa. Examination of the bark extract of Ancisirocladus lectorius (Ancistrocladaceae) collected in Johore. Peninsular Malaysia, resulted in the isolation of a new simple isoquinoline, 6,8-dimethoxy-3-hydroxymethyl-1 -methylisoquinoline (1) and a new naphthylisoquinoline derivative, 4 -O-demethylancistrocladine (4), together with the known isoquinolines, 6,8-dimethoxy-l,3-dimethylisoquinoline (2) and (5)-6,8-dimethoxy-l,3-dimethyl-3,4-dihydroisoquinoline (3) [24, ... 

The paper reporting the reaction of isoquinoline and potassium cyanide with dialkyl chlorophosphates and dialkyl chlorothiophosphates to give products of the type 114 has now appeared. These compounds can be alkylated in the same manner as a normal Reissert compound, and hydrolysis of the alkylation product gives 1-methylisoquinoline. A phthalazine analog (115) has also been prepared. ... 

Determinations of the ERE of quinoline from thermochemical data have given results which range from 47.3 to 69 kcal mole-1.49-271-272 There appear to be no corresponding estimates for isoquinoline, but a value of 48 9 kcal mole-1 has recently been deduced from a comparison of the equilibrium constants for pseudo-base formation of iV-methylisoquinoline cation and its dihydro analog 73.273 Comparison of these ERE values with those obtained for naphthalene (61-75 kcal mole-1) shows that they parallel the somewhat lower resonance energy of pyridine relative to that of benzene. 

Treatment of isoquinoline with sulphuryl chloride and potassium cyanide gives 4-chloro-l-cyanoisoquinoline and l-carbamoyl-3-cyanoisoquinoline, the relative yields of the two products depending upon the proportion of reagents. The Reissert compound from 4-methylisoquinoline gives the bromohydrin (172), and this, on treatment with aqueous sodium hydroxide, affords the benzoylimino-compound (173). Hydrolysis of the latter with dilute hydrochloric acid yields 4-methylisocoumarin (174) (Scheme 71). ... 

The alkaloid anhalonine was generated by methylation of the corresponding l,2,3,4-tetrahydro-6,7-dimetoxy-8-hydroxy-l-methylisoquinoline (anhaloni-dine) Kreysigine, a benzocyclohepta-isoquinoline alkaloid, was obtained by the methylation of l,10-dihydroxy-2,l l,12-trimethoxy-4,5,6,6a,7,8-hexahydrobenzo[6,7] cyclohepta [l,2,3-(/]isoquinoline (floramultine alkaloid) (Figure 1.5d). 

Another structure mentioned several times in the literature as a suitable substrate for 6- xo-cyclizations is substructure G (Figure 6.4) [108, 109]. Larock and Babu [110] prepared 4-methylisoquinoline (143) from A-(but-3-enyl)-2-iodoaniline (142) under very mild conditions in nearly quantitative yield (Scheme 6.40). The cyclized compound completely isomerizes to the aromatic isoquinoline no xo-cyclic product could be detected. It is worth mentioning that the reaction proceeds cleanly without a protecting group on the secondary amine, a group which has been known to cause problems during intramolecular cyclizations if left unprotected [8]. 

Several possible mechanisms including ionic [39] and free radical [40] formation have been proposed for the analogous rearrangement of 2-picoline N-oxide. In the case of the isoquinoline series, where no rearrangement products at position 3 were isolated, an intermediate (74) resulting from abstraction of an active H from the 1-methyl by AcO would be reasonably expected to predominate in the transformations. Such an intermediate cannot be formed from 3-methylisoquinoline since it would result in the disruption of the aromaticity of the benzene ring. Conversion of (74) to the 1-acetoxymethyl derivative (75, pathway a) may result from an intramolecular rearrangement, analo-... 

Exceptionally, there is an example for simultaneous construction of both benzene and pyridine rings toward a perfluorinated isoquinoline. Feast et al. reported the synthesis of perfluoro-3-methylisoquinoline via the hetero Diels-Alder reaction of perflu-oro-l,4,6,7-tetrahydro-l,4-ethanonaphthalene with trifluoroacetonitrile followed by pyrolysis, which involved elimination of tetrafluoroethylene (Scheme 25) [93]. 

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