Dihydroisoquinoline A-oxides

It is noteworthy that quick and effective formation of diaryl nitrones can be achieved through oxidation of diaryl imines with Oxone (potassium peroxy-monosulfate) in such media as aqueous solution of NaHCC>3 in acetonitrile or acetone. When oxidized under such conditions, dialkyl or monoaryl imines give oxaziridines (17). Oxidation of 3,4-dihydroisoquinoline (9) with Oxone initially leads to the formation of oxaziridine (10) which is easily transformed into the corresponding 3,4-dihydroisoquinoline A-oxide (11) upon treatment with catalytic amounts of p-toluenesulfonic acid (Scheme 2.4) (18). 

The /V -hydroxylamino compounds (404) and (405), obtained from the reaction of tert-butyl acetate with 3,4-dihydroisoquinoline-A-oxide or 5,5-dimethyl-pyrroline-/V-oxide, when boiled in methylene chloride in the presence of triphenylphosphine, carbon tetrachloride and triethylamine, are transformed to (1,2,3,4- tetrahydroisoquinolin-l-ilidene) acetate (406) or (pyrrolidin-2-ilidene) acetate (407) (Scheme 2.181) (645). 

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]. 

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

Vinylzinc reagents have been added to 3,4-dihydroisoquinoline A-oxide (24) in up to 95% ee, using a chiral 2-aminoamide as auxiliary.59... 

The reaction of 3,4-dihydroisoquinoline A-oxide (74) and methacrylonitrile in the presence of cationic half-sandwich rhodium and iridium complexes containing a chiral diphosphine ligand was analyzed. The cycloadditions occurred with excellent regio- and diastereoselectivity and low-to-moderate enantioselectivity. Analysis of the catalytic system showed the formation of two epimeric complexes 75 containing the dipolarophile methacrylonitrile. The reaction of one of the isolated diastereopure complexes 75 with 74 afforded cycloadduct 76 with high enantioselectivity. A recycling procedure was developed in order to increase the adduct/catalyst ratio <07CEJ9746>. 

The 1,3-dipolar cycloaddition of allenes with 3,4-dihydroisoquinoline A -oxides yields the isoxazolidine-fused 1,2,3,4-tetrahydroisoquinoline <97JCS(P1)2973, 97T9575,... 

A review of recent developments in 1,3-dipolar cycloaddition of nitrones with sila-, thia-, phospha-, and halo-substituted alkenes has been reported. A DFT study of solvent effects on the intermolecular 3-l-2-cycloaddition reaction of norbornadiene with 3,4-dihydroisoquinoline A(-oxide at 398.15 K indicated that the reaction proceeds via a synchronous concerted mechanism. Chiral imidazolidinone salts, in the absence of water, promote the 1,3-dipolar cycloaddition reaction of alanine-derived ketonitrones... 

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). 

Treatment of 3,4-dihydroisoquinoline-2-oxides (730) with DMAD in toluene at room temperature gave the corresponding isoxazolo[3,2-a]isoquinolines (731). On heating in toluene, they were converted to the corresponding ylides (732) in high yields (Scheme 2.304) (27b). 

The isoquinoline ring undergoes attack by the nucleophilic aluminum hydride anion in much the same manner as the pyridine ring to produce 1,2-dihydroisoquinolines,91,92 although tetrahydroisoquino-lines have been reported as products even though no proton source was apparently present.92 (For a probable mechanism see Section IV,B.) The reduction of isoquinoline A-oxide by lithium aluminum hydride was also reported to yield the 1,2-dihydroisoquinoline.93... 

Additions have been reported for both cyclic aldo- and keto-nitrones and have been utilized in the synthesis of structurally diverse heterocyclic systems (see Table 17). The condensation of 3,4-dimeth-oxybenzyl Grignard with 3,4-dihydroisoquinoline N-oxide (entry 1, Table 17) provides an access to pellefierine alkaloids.A synthetic use of cyclic ketonitrone condensations is demonstrated in the addi-... 

A-oxide.10 1,2-Dihydroisoquinolines themselves are slowly reduced by LAH to form 1,2,3,4-tetrahydroisoquinolines (8).13... 

Meutermans and Alewood [48] reported the solid-phase synthesis of tetrahydroisoquinolines 13 and dihydroisoquinolines 13a using the Bischler-Napieralski reaction (Fig. 5). The polystyrene resin-bound deprotected L-3,4-dimethoxyphenylalanine was acylated with acetic acid derivatives using N- [(IH-benzotriazol-1 -yl)(dimethylamino)methylene] -iV-methylmethana-minium hexafluorophosphate A-oxide (HBTU) as a coupling reagent. The product obtained was then treated with phosphorus oxychloride under optimized conditions to afford a Bischler-Napieralski cyclization. Hutchins and Chapman [49] reported the synthesis of tetrahydroisoquinolines 13b and 4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridines 14 via cyclocondensation of the appropriate dipeptidomimetic with various aldehydes (Fig. 6). 

Several sugar-derived N-hetcrocycles have been reported castanospermine analogues 29-31, 1-deoxynojirimycin.HQ, the carbohydrate-derived dihydroisoquinoline-/V-oxide 32, and lV-trideca-5,7-diyne-D-glucosainine (a super-structure fomiing synthetic glycolipid) at 295, 100 and 20K.100... 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Bischler-Napieralski reaction of 139 to a 3,4-dihydroisoquinoline, oxidation, dehydrogenation and reduction of the nitro to the amino function gave 140 which was subjected to a Pschorr reaction (Scheme 49). Quaternization was accomplished by methyl iodide to furnish the isoquinolininium salt 141 which underwent an ether cleavage on heating a solid sample or benzene or DMF solution to Corunnine (127) (73TL3617). 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

Reaction of pure (5ir,/ c)-9 with nitrones IV or V followed by the addition of an excess of n-Bu4NBr (Scheme 21) gives the corresponding 3,5-crt(io-isoxazolidines in quantitative yield. Table 5 collects the ee values obtained for the two nitrones. Comparison of the results of Table 5 with those of Table 4 indicates that, whereas a mixture of epimers complex 9 (67% / ir,/ c/33% 5ir,/ c, molar ratio) reacts with nitrones 2,3,4,5-tetrahydropyridine /V-oxide (IV) or 3,4-dihydroisoquinoline... 

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