3.4- Dihydroisoquinoline, synthesis from

Nitrogen Heterocycles.- Intramolecular Wittig reactions have been used to construct heterocyclic rings in, for example, the synthesis of N-alkyl-3-pyrrolines (193) (Scheme 18) and that of 2-methyl-3-(aryl/alkyl)-l-oxo-l,2-dihydroisoquinolines (195) by a one-pot synthesis from the amides (194) (Scheme 19). ... 

The structure of ankorine (130) has been revised following a successful total synthesis from the dihydroisoquinoline (127) as shown (Scheme 2). The previously assumed structure with the hydroxy-group in position 8 of the isoquinoline system was shown to be incorrect by synthesis of all four possible stereoisomers of the corresponding isomer of (130). "... 

The Bischler-Napieralski synthesis of l-methyl-3,4-dihydroisoquinoline (18) from N-(2-phenylethyl)acetamide (19) in the presence of heat and acid (72) was not predicted by the Electrophilic Aromatic module of CAMEO this module of CAMEO predicted instead the formation of methyl 2-acetyl-phenethylamine, 20 (Scheme 5). In a related case, CAMEO predicted (when the Electrophilic Aromatic module was chosen) that 4-anilino-butan-2-one (21) would undergo intramolecular cyclization to form 4-hydroxy-4-methyl-tetrahydroquinoline, 23 (Scheme 6). Apparently, CAMEO correcdy perceives the eneamine character of 21 as necessary for this reaction to occur. It was noted in this case that ring formation, as predicted by CAMEO, depended upon the presence of mineral acid, but did not occur if a Lewis acid (e.g., stannic chloride) was selected instead as the reagent. It is known, however, that intramolecular cyclization of 21 does occur in the presence of a Lewis acid and yields 4-methyl-quinoline, 22, as product (74). 

Scheme 5. Synthesis of l-Methyl-3,4-dihydroisoquinoline (18) from N-(2-Phenylethyl)acetamide (19)...

Cyclizations of ene—yne ketenes were su ested for the synthesis of dihydroisoquinoline 335 from 331 via the intermediate ketene 332 with subsequent oxidation in the degassed refluxing xylenes and modest dilution conditions (0.01—0.02 M concentrations), furnished the triones 335a—fin satisfactory yields as the only obviously identified products (Scheme 104) (1995JOC6460, 1999JOC6881). Formation of trione 335h shows that a sterically hindered amide is appropriate for ring closure if the amide... 

The same conditions may be applied to the synthesis of dihydroisoquinolines 15 from 2-alkynylbenzylamides 14 (Scheme 5). 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

Total synthesis of polycarpine (73) from commercially available materials was performed by Lenz end Woo (75) (Scheme 21). The key intermediate in this synthesis was dihydroisoquinoline 82, which on treatment with mixed formic-acetic anhydride and removal of the blocking group was converted to 73. In a similar way polycarpine methyl ether was synthesized and used as intermediate in photosynthesis of protoberbine derivatives (85). 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quatemarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 5 mixture of formic acid and phosphorous acid gave ( )-platycerine (89) in 60-70% yield. 

A Once the 1,2-dihydroisoquinoline is formed by a Potneranz-Friisch synthesis between the reduced imine, from 4-methoxybenzaldehyde and ami noacetaldehyde diethyl acetal, it is combined directly with the l-(2-bromoethyl)-3-meihoxybenzene in a tandem two-steps-in-one procedure (Scheme 3.21), First the compound acts as an enamine and combines with the alkyl bromide at C-4, and then the methoxylated phenyl ring of the intermediate reacts with the iminium unit at C-3 to form the letracycle. 

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... 

Triflic anhydride is a useful reagent for the preparation of covalent triflate esters from alcohols, ketones, and other organic substrates [66] In many cases, very reactive Inflates can be generated in situ and subjected to subsequent transformation without isolation [94, 95, 96, 97] Typical examples are cyclization of amides into dihydroisoquinolines (equation 45) and synthesis of N-hydroxy-a-amino acid derivatives (equation 46) via the intermediate covalent triflates... 

Dimethoxy-3-hydroxypavinane (13) (C19H2103N mp 197-198° [a]n7 — 254°) was isolated from this plant. Its structure was confirmed by a total synthesis involving the penultimate 1,2-dihydroisoquinoline and its cyclization with formic and phosphoric acids (10). 

This version also permits a one-pot synthesis of dihydroisoquinolines or P-carbo-lines from 2-arylethylamines and carboxylic acids. 

The use of Sc(OTf)3 as the catalyst facilitated the Skraup synthesis of 1,2-dihydroquinolines from anilines and a variety of dialkyl ketones at mild conditions (room temperature). Nevertheless, an elevated temperature was necessary if acetophenone was employed in the cyclo condensation with anilines [109]. Microwave dielectric heating at 150 °C for 50 min was sufficient to bring about the formation of the desired 1,2-dihydroisoquinolines (Scheme 40). 

The synthesis (Eq. 2) of a Zl -pyrroline was achieved by a procedure189 190 similar to the Bischler-Napieralski preparation of 3,4-dihydroisoquinolines from A7-acyl phenethylamines. 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

Dehydrobromination of 174 with lithium bromide in dimethylformamide gave the tribromo-4-azaazulenone 11 in good yield (69JCS(C)1028). In a one-pot synthesis, the lactam 177 was obtained from the dihydroisoquinoline 175 and the benzoyl chloride 176 (84TL3485). 

Because isoquinolines are dealt with in more detail in Chapter 51, we will give just one important synthesis here. It is a synthesis of a dihydroisoquinoline by what amounts to an intramolecular Vilsmeier reaction in which the electrophile is made from an amide and POCI3. Since, to make the isoquinoline, two hydrogen atoms must be removed from carbon atoms it makes more sense to use a noble metal such as Pd(0) as the oxidizing agent rather than the reagents we used for pyridine synthesis. 

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