3.4- Dihydroisoquinolines, preparation

B. 2-Acetyl-6,l-dimethoxy-l-methylene-l,2,3,4-tetrahydroisoquinoline [Isoquinoline, 2-acetyl-l,2, A,4-tetrahydro-6,7-dimethoxy-l-methylene-]. A 1-1., three-necked, round-bottomed flask equipped with a mechanical stirrer, a reflux condenser topped with a calcium chloride drying tube, and a thermometer is charged with 110 ml. of acetic anhydride, 110 ml. of pyridine, and 45.0 g. (0.22 mole) of the dihydroisoquinoline prepared in Part A. The reaction mixture is stirred and heated at 90-95° for 30 minutes, stored at room temperature overnight, and concentrated by distillation at 50° using a rotary evaporator. The residue is diluted with 20 ml. of ethyl acetate, and another evaporation under reduced pressure gives material that can be crystallized from 75 ml. of ethyl acetate to yield 38.5 41.0 g. (72-77%) of product, m.p. 106-107° (Note 11). 

The Bischler-Napieralski reaction was employed by Bonjoch in the synthesis of melinonine-E and strychnoxanthine. The preparation of polycyclic compound 57 was achieved in 53% yield by treating 56 with POCI3 followed by reduction of the dihydroisoquinoline with NaBIii. 

All these syntheses form variations of the same reaction. The three-membered ring is formed from an A-halogenoamine with ketone-ammonia mixtures or the Schiff s base 3,4-dihydroisoquinoline. Starting from these first observations the three groups of authors were able to generalize their diaziridine syntheses quickly in the years 1959-1962 they were extended to generally applicable reactions. In numerous variations of the syntheses, large numbers of diaziridincs were prepared. 

Dialkyl-diaziridines are not attacked by lithium aluminum hydride l,2-di-n-butyl-3-n-propyldiaziridine (60) was recovered in 80% yield after treatment with lithium aluminum hydride in boiling ether. A preparative separation of 34 and 3,4-dihydroisoquinoline is possible by treating the mixture with lithium aluminum hydride when compound 34 is unattackcd. ... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

A solution of 50 grams of N-(a-methylhomoveratryl)-3-methoxy-4-ethoxyphenylacetamide, prepared as set out above, in 200 cc of benzene, is treated with 8 cc of phosphorus oxychloride. The mixture is refluxed for about 3 hours, cooled and then is shaken with a solution composed of 15 grams of sodium hydroxide dissolved in 60 cc of water. The aqueous layer is removed, and the benzene solution is washed with water. The washed benzene solution is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The low-melting solid residue is 6,7-dimethoxy-3-methyl-1-(3 -methoxy-4 -ethoxybenzyl)-dihydroisoquinoline base. 

The, g 7M-dibroniodihydrocyclopropa[r]isoqiiinolines 8 (R = H, Cl), prepared by addition of dibromocarbene to the corresponding 2-acctyl-l-phcnyl-l,2-dihydroisoquinolines, in the presence of silvcr(I) trifluoioacetate, undergo rearrangement to the 5/f-2-bcnzazepines 9, albeit in poor yields.3... 

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

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 same rhodium precursor, (S Rh,/ c)-[(Tl -C5Me5)Rh (l )-Prophos (H20)] (SbFg)2, promotes the reaction between the nitrones A-benzylideneaniline A-oxide or 3,4-dihydroisoquinoline A-oxide with other enals different from methacrolein (Scheme 10). The cycloadducts were prepared with excellent regioselec-tivity, perfect endo selectivity, and enantiomeric excesses up to 94% [35]. 

Substituted nitrosoalkenes, prepared in situ from corresponding a-bromo oximes, can be added to furan , pyrrole or indole to afford fused oxazine derivatives. Recently, there was reported a preparation of novel heterocyclic oxazinotetrahydroquinoline 355 and 356 or oxazinotetrahydroisoquinoline 357 derivatives by reaction of the corresponding dihydroquinolines or dihydroisoquinolines with a-bromo oximes 354 in the presence of NajCOj in CH2CI2 (equation... 

Several 1-benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide 17). Similarly, es-cholamine (37) has been prepared from A-benzoyl-l-cyano-6,7-meth-ylenedioxy-1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzyl chloride (77) as shown in Scheme 6. 

This method is very useful for the construction of 1-substituted 3,4-dihydroisoquinolines, which if necessary can be oxidized to isoquinolines. A P-phenylethylamine (l-amino-2-phenylethane) is the starting material, and this is usually preformed by reacting an aromatic aldehyde with nitromethane in the presence of sodium methoxide, and allowing the adduct to eliminate methanol and give a P-nitrostyrene (l-nitro-2-phenylethene) (Scheme 3.17). This product is then reduced to the p-phenylethylamine, commonly by the action of lithium aluminium hydride. Once prepared, the p-phenylethylamine is reacted with an acyl chloride and a base to give the corresponding amide (R = H) and then this is cyclized to a 3,4-dihydro-isoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride (Scheme 3.18). Finally, aromatization is accomplished by heating the 3,4-dihydroisoquinoline over palladium on charcoal. 

Through a slight modification the Pomeranz-Fritsch synthesis can be made particularly useful for the preparation of 1,2-dihydroisoquinolines. The imine is first reduced with sodium borohydride in 98% ethanol to the corresponding benzylamine, prior to cyclization, by treatment with 6 M hydrochloric acid. When electron-donating groups (such as a methoxyl) are present in the aromatic unit of the benzylamine, the ring-... 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

Dihydroisoquinolines, e.g. (484), are basic and form quaternary salts, e.g. (521). With alkali these salts form carbinolamine pseudo-bases, e.g. cotamine (522 Y = OH), which can be oxidized to lactams or which disproportionate on standing. The quaternary ions can also react with other nucleophilic reagents, e.g. (521) + RMgBr — (522 Y = R) (521) + MeCOMe — (522 Y = CH2COMe) (521) + CN — (522 Y = CN) (521) + RNH2 —+ (522 Y = NHR). The pseudo-bases are in equilibrium with open-chain compounds since aldehyde derivatives can be prepared. 

Treatment of 3-[(3-chloropropyl)amino]-l,4-dihydroisoquinoline hydroiodide (191), prepared from 3-methylthio-l,4-dihydroisoquinoline hydroiodide and 3-chloropropylamine, with a mole equivalent of boiling 1 N ethanolic sodium ethylate for 24 h, then with picric acid afforded 3,4,6,11-tetrahydro-2//-pyrimido[l,2-6]isoquinoline picrate (192) (88MI3). 

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... 

The synthesis of heterocycles is another common application of the Ritter reaction. Equations (168 -(170) illustrate the preparation of a lactam,236 oxazoline237 and dihydroisoquinoline,235 respectively. 

The isoquinoline system is conveniently prepared from treatment of o-iodobenzylamines with the enolate ions derived from symmetrical ketones (or ketones with one a-position blocked), aldehydes, or the dimethyl acetal of pyruvaldehyde, to give aminocarbonyl compounds which condensed in situ to give 2- and/or 3-substituted 1,2-dihydroisoquinolines. Catalytic dehydrogenation or borohydride reduction of these products then led to the corresponding isoquinolines or tetrahydroisoquinolines in moderate to high... 

Silver ion-promoted ring enlargement of the l-tribromomethyl-l,2-dihydroisoquinoline 334 (prepared from 333, which was accessed in turn from isoquinoline) resulted in a compact approach to the 3-benzazepin-2-ones 335 (Scheme 44) <2003TL4203>. 

These structures were confirmed by syntheses. The amide 3 prepared from known compounds was reacted with phosphorus oxychloride in acetonitrile to generate a dihydroisoquinoline which on reduction, diazotization, and treatment with activated copper gave dihydro-imeluteine. Dehydrogenation to the natural alkaloid was effected by... 

The isoquinoline ring has been shown to be selectively reduced to the dihydro- or tetrahydroisoquinoline by diisobutylaluminum hydride, depending upon the ratio of reducing agent employed. The reaction has been employed to prepare 1,2-dihydroisoquinoline or... 

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. 

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