Dihydroisoquinolin-3-ones

Alkylation of the lactam 92 via its enolate has been studied and shown to be highly stereoselective. The 4-substituted l,4-dihydroisoquinoline-3-one 93 was obtained in high yield with greater than 97% de <96T(A)(7)417>. 

In 2011, Xi and co-workers described a copper-catalyzed one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(lH)-ones by using ort/zo-bromobenza-mides and isothiocyanates as substrates. Various 2-thioxo-2,3-dihy-droquinazolin-4(lff)-ones were conveniently synthesized in moderate to excellent yields with Cul as a precatalyst, CS2CO3 as a base, iV// -dimethy-lethane-l,2-diamine as a ligand, and toluene as a solvent, with the reaction temperature at 120 °C. Yu s group reported a novel procedure for the synthesis of 4-substituted-l,4-dihydroisoquinolin-3-ones and evaluated their antitumor activities (Scheme 3.62). ... 

Applying the same methodology, Felpin et al. reported the selective synthesis of 4-benzyl-l,2-dihydroisoquinoline-3-ones by the reaction of 2-(2-cyanoaryl)acrylate instead of 2-(2-nifrophenyl) acrylafe and aryl diazonium salt [31]. 

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... 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The synthesis of 3,4-dihydroisoquinolines via intramolecular reactions of phenethyl amides was first reported by August Bischler and Bernard Napieralski in 1893. The authors described the conversion of A-acyl phenethylamide (1, R = Me) and A-benzoyl phenethylamide (1, R = Ph) to 1-methyl-3,4-dihydroisoquinoline (2, R = Me) and 1-phenyl-3,4-dihydroisoquinoline (2, R = Ph), respectively, in the presence of P2O5. This reaction has subsequently proven to be one of the most general methods ever developed for the synthesis of dihydroisoquinolines. 

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 wide variety of other functional groups can be employed in these annulations. For example, this chemistry has been extended to the synthesis of 1,2-dihydroisoquinolines, benzofurans and benzopyrans (Scheme 3).3 One can also employ vinylic halides and triflates in this process.4... 

Another chemotype displaying appreciable isoform selectivity is the 5-benzoyloxy-3,4-dihydroisoquinolin-l(2H)-one (37), displaying ICso = 0.8 and 13 pM against PARP-2 and PARP-1, respectively [36]. Interestingly, 38 is a selective PARP-1 inhibitor, pICso = 7.35, displaying around 100-fold selectivity for PARP-1 over PARP-2 [34],... 

An improved method for the synthesis of 4-hydroxy-1-oxo-l,2-dihydroisoquinoline-3-carboxylic acid derivatives 130 was presented <06S1971>. This improved three-step method efficiently converts phthalic anhydride 131 to the desired dihydroisoquinolines 130 in high yields over three steps with only one purification. 

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). 

Stereochemical control of a reaction can also be achieved using non-chiral catalysts, when a chiral centre already exists in the reactant, as for example in the reaction of cyano- or methoxycarbonylmethyl phosphonates with 3-hydroxy-2-(S)-alkylated products are obtained with ca. 40% de of the 2(S)-3(R)-diastereoisomers [11]. Similarly, when ethyl glycine is Ar-protected with (S)-menthone, C-alkylation under soliddiquid conditions using a non-chiral catalyst (6.4.5) provides a route to chiral a-substituted amino acids with optimum enantiomeric excesses of up to 47% [12],... 

Reaction of alkylphosphonates with chiral 2-substituted 3-hydroxy-3,4-dihydroisoquinolin-1-one... 

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. 

The l,3,4-oxadiazin-6-one (240) undergoes cycloaddition followed by a remarkable rearrangement to give the triazole A(-imine 241 and an open-chain product (136). Cycloadditions have also been carried out with the following ring systems 1,2-dihydroisoquinoline (242) (137) dihydro-1,3-oxazine (243) (138,139), 2H-, 3-benzothiazine (244) (140,141), and 27/-l-pyran-2-thione (245) (142). 

Much more work has been done on the cyclization of amides, mainly of enamides. There are examples of the use of N- chloroacetylbenzylamines to produce dihydroisoquinolin-4-ones (220) (74TL1181). Irradiation of enamides (221) can give either tetrahydrophenan-thridinones (71JOC3975) or hexahydrophenanthridinones (74JCS(P1)1747). Without added iodine a mixture of cis and trans derivatives is obtained and the ratio varies with solvent in non-polar solvents the trans cis ratio can be 15.6 1. If iodine is added to the solution to be irradiated, the quinol-2-ones are obtained. The mechanism has been discussed and... 

The photochemical electrocyclization of conjugated iminium salts 160, formed by protonation of 2-azadienes 159, led to isoquinolin-4-ones 162, presumably through hydrolysis and oxidation of the dihydroisoquinoline intermediates 161 (85TL5213) (Scheme 39). A closely related reaction served as the key step for a short synthesis of the pentacyclic marine alkaloid ascididemin as reported by Moody, Rees, and Thomas [90TL(31)4375 92T3589] the central reaction involves a 67r-electron pho-tocyclization of a syn- aza stilbene in sulfuric acid. 

A dihydroisoquinoline was at one time investigated in some detail as an antiviral compound. Acylation of 3-phenethylamine (52-1) with 2-(4-chlorophenoxy)acetyl... 

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