1.2- Dihydroisoquinolines formation

Leptopinine 82 possesses the 3,4-dihydro-isoquinolin-7-ol moiety without further conjugation and was isolated as yellow powder from Hypecoum leptocarpum after several extractions with hydrochloric acid so that this alkaloid was finally isolated as a chloride (Scheme 29). The formation of a mesomeric betaine from this dihydroisoquinoline derivative is unlikely because on addition of base no significant changes of the UV spectra were observed (99P339). A similar structure is Pycnarrhine Pycnarrhena longifolia), which was isolated as a hydroxide (81P323). 

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). 

Additional examples of these novel SET-promoted photorearrangement reactions were uncovered in our investigations with the 2-azadienes 78 and 82. These substances yield the corresponding A-vinylaziridines 93 and 94, respectively, upon DCA-sensitized irradiation (Structures 93-99). The study was extended to azadiene 73. The DCA-sensitized irradiation of 73 yields the aziridine 95 and the dihydroisoindole 96 [65]. However, under these conditions, 2-azadiene 97 affords, in addition to the expected aziridine 98, the dihydroisoquinoline 99. The formation of the isoindole 96 can be explain by a pathway in which a radical-cation centered on the C—double bond attacks the phenyl ring at C-3, as shown in Scheme 15. The formation of the dihydroisoquinoline 99 can be justified by... 

The synthetic process leading to pavine formation can now be illustrated as in Scheme 1. It includes quatemization and selective reduction of the iminium bond to afford a 1,2-dihydroisoquinoline (36), which is the key intermediate in the synthesis of pavine bases. Acid-catalyzed cyclization of this enamine furnishes the pavinane framework 38 via the 1,4-dihydroisoquinolinium ion 37. Langhals... 

Polystyrene-bound o-quinodimethanes, which are formed upon thermolysis of ben-zocyclobutanes, can be converted into 1,2,3,4-tetrahydroisoquinoline derivatives by reaction with /V-sulfonylimines. Reaction of o-quinodimethanes with electron-poor nitriles leads to the formation of 1,4-dihydroisoquinolines, which undergo elimination with simultaneous release of isoquinolines into solution (Entry 7, Table 15.25). 

Evidently, the stability of 3-hydroxy-3,4-dihydroisoquinolines 137, formed as the result of heterocyclization, is also determined by the anne-lated benzenoid ring. The lower tendency toward aromatization for these compounds, compared to monocyclic analogs, leads to the ability of 137 to react as a cyclic azomethine. The addition of a molecule of nucleophile to the C=N bond causes opening of the isoquinoline ring and formation of a new ring system (for instance, a-naphthols 141 in alkaline aqueous solutions). Such conversions occur even under conditions of the recyclization reaction of 2-benzopyrylium salts, namely, on heating 137 in alcoholic ammonia a mixture of isoquinoline 138 and a-naphthylamine 140 results (88MI1). 

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 best catalyst for this transformation was AgSbFg (10 mol%), and (3-ketoesters, malonates, and silyl enol ethers have been used for the nucleophilic addition on the pyridinium intermediate DD. The dihydroisoquinolines 48 have been further used in several reactions in order to assemble the framework of various alkaloids. One example is given in the formation of dihydroisoquinoline 49, bearing a pendent a, 3-unsaturated ketone. Compound 49 can rearrange to the tetracycle 50 (related to the core structure of karachine, Scheme 5.23), using TMSOTf, via a tandem Michael addition-Mannich reaction process (intermediates EE and FF). 

The reduction of isoquinolinium ions has been extensively investigated with borohydride and aluminum hydride ions. The use of boro-hydride ion in a protonic solvent normally leads to the formation of 1,2,3,4-tetrahydroisoquinolines, whereas the reduction with aluminum hydride ion in an aprotic medium generally gives a 1,2-dihydroiso-quinoline. This 1,2-dihydroisoquinoline contains an enamine system and may undergo further reaction on treatment with acid. The 1,2-and 3,4-dihydroisoquinolines as well as isoquinolinium ions are reduced by the borohydride ion in a protonic medium to the 1,2,3,4-tetrahydroisoquinolines. 

The imidazolyl-annelated dihydroisoquinoline 78 was accessible from the cyclization of imidazole 79. The outcome of intramolecular substitutions on pyridines turned out to be strongly dependent on the linker between the aromatic cores (Scheme 30). With a c/.v-configured alkene in place, as in 80, the expected benzoisoquinoline 81 was isolated in excellent yield. The frans-configured alkene and the saturated C2-alkane were shown to be less suitable tethers due to the formation of side products. 

The Vilsmeier reaction,103 which has been successfully applied104 to the formation of 3-acylindoles, has yielded the 4-formyl-1,2-dihydroisoquinolines (76)—(78).105—10 d. Reactions with Aldehydes. Cyclopentanone enamine gives the... 

The l-benzyl-l,2-dihydroisoquinoline [(138) R = OH, R = OMe] has been rearranged,116 and the structure of the product (140) proved by synthesis.147 The threshold for pavine formation versus migration... 

The reduction of quinoline with either lithium or sodium in liquid ammonia produces only 1,4-dihydroquinoline366. Formation of 1,2-dihydroisoquinolines was observed in the reduction of quaternary isoquinoline salts with sodium hydrosulphite367, lithium aluminium hydride368-370, NaBH4371, dialkylaluminohydrides372 or on treatment with a Grignard reagent373. 

A mechanism similar to the one described for the formation of 1,3,4-oxadiazolines from tetrazoles and carbonyl compounds is postulated also for the reaction of hexahydrotetrazine derivatives in the 3,4-dihydroisoquinoline series with carbonyl compounds. 

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>. 

Sequential reaction of azines with alkyl hthium compounds and chloroformates usually affords the expected Reissert-type products 136, together with minor amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely to react directly with the alkyl-lithium compound to generate the alkylated lithio-enamine intermediate E, and this species may account for the formation of dihydroisoquinolines 135 and 136, through interaction with the electrophihc partner. Mamane recently expanded this concept by replacing the acylating agent with different electrophiles. These combinations lead exclusively to isomers 134 (Scheme 18) [118-120]. 

The reduction of isoquinolinium salts in aprotic solvents with LAH leads to the formation of 1,2-dihydroisoquinolines (195), in which the enamine system can undergo subsequent reaction with electrophiles. This type of reactivity has been exploited in the synthesis of alkaloids. ... 

In 1952, Ritter and Murphy reported cases of intramolecular Ritter behavior resulting in formation of dihydroisoquinolines from reactions of methyleugenol with nitriles such as veratronitrile (equation 30). Such reactions involve nucleophilic attack by the aromatic ring on the nitrilium ion and are enhanced by... 

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