Dihydroisoquinolinium salts

While 3-arylisoquinolin-l(2fl)-ones 87 are obtained by air oxidation of 3,4-dihydroisoquinolinium salts, the use of DDQ in dioxane results in a selective dehydrogenation to the corresponding -substituted isoquinolinium salts 88 <95T(51)12721>. 

An advantage of the modified Pomeranz-Fritsch synthesis is that the 1,2-dihydroisoquinolines can be reacted in situ with electrophiles, yielding 1,4-dihydroisoquinolinium salts that react with nucleophiles at C-3 (see Section 3.3.3). Such a single pot procedure can be used to form complex 1,2,3,4-tetrahydroisoquinolines. 

Anodic oxidation of 4-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-l,2, 3,4-tetrahydroisoquinoline (168) in trifluoroacetic acid-dichloromethane-Bu4NBF4, using controlled-potential electrolysis (-I-1.2V versus SCE) affords the corresponding 3,4-dihydroisoquinolinium salt (169), and the 4-(3,4-dimethoxybenzylidene)-6,7-dimethoxy-2-methyl-3,4-dihydroisoquino-linium salt (170) was formed at higher anodic potential (+1.9V versus SCE) at a carbon-felt anode256 [Eq. (104)]. 

Oxidation of 2-(3-aminopropyl-l,2,3,4-tetrahydroisoquinoline with mercuric acetate in 4% aqueous acetic acid at 50°C for 6 h, and then at room temperature overnight followed by the treatment of the filtered solution with 20% potassium hydroxide solution, yielded 1,3,4,6,7,llb-hexahydro-2//-pyrimido[2,l-a]isoquinoline (16, R = R1 = H) in 27% yield (73JOC437). 1,3,4,6,7,llb-Hexahydro-2//-primido[2,l-a]isoquinolines (16, R = H, MeO, R1 = H) and their 2-oxo derivatives (18, R = H, MeO, R1 = H) were obtained from 2-(3-aminopropyl)- and 2-(2-aminocarbonylethyl)-3,4-dihydroisoquinolinium salts (17 and 19, R = H, MeO, R1 = H) by treatment with a base (62CB2122,62MI1). The adjustment of the pH value of a solution of l-methyl-2-(2-aminocarbonylethyl)-3,4-dihydroisoquinolinium perchlorate (19, R = H, R1 = Me, X = C104) in 10% aqueous acetic acid with sodium carbonate to 9 yielded 1 lb-methyl-1,3,4,6,7,1 lb-hexahydro-2//-primido[2,l-a]isoquinolin-2-one (111) (93KGS499). 

As shown by Verin et al. [90KGS(ip2)], the reaction of azomethines with 2-benzopyrylium salts 30 having substituents other than a methyl group in position 1 results quantitatively in 3,4-dihydroisoquinolinium salts 238. Interestingly, isoquinolinium salts of type 152 and their ben-zenoid analogs do not react with such weak dienophiles as azomethines. 

Benzopyrylium salts are more suitable than homophthalic anhydrides for the synthesis of dihydroisoquinolinium salts of type 237, by the method described previously, because of the easier availability and greater variety of the former compounds. 

Benzo[c]pyrylium salts (e.g., 135) also undergo cycloadditions with azomethines via the intermediacy of 136 and 137 to give dihydroisoquinolinium salts such as 138 (Scheme 15) <1997MC204>. 

Treatment of the dihydroisoquinolinium salt 699 with Hiinig s base (/-PrzNEt) produces the corresponding azomethine ylide, which can undergo intramolecular cycloaddition with the tethered alkyne to afford the chro-meno[3,4- ]pyrrol-4(3//)-one 700 in high yield. Subsequent deprotection of the isopropyl protecting groups affords the marine natural product lamellarin K (Scheme 173) <1997CC2259>. 

In 1963, it was reported188 that when 2-methyl-1,2-dihydro-papaverine [(133) R = OMe] is treated with dilute acid (2% HC1 or acetic acid) at 100° for 30 minutes, a high yield of the 2-methyl-3-benzyl-3,4-dihydroisoquinolinium salt [(134) R = OMe] is formed. 

The pentacyclic pyrrole-containing systems lamellarins U 40 and L 41 have been synthesized on solid phase, involving a [3 + 2] cycloaddition of a 3,4-dihydroisoquinolinium salt with an alkyne as the pyrrole ring-forming key step <03OL2959>. In another application... 

In order to demonstrate the transfer of a benzyl group to an acceptor under the rearrangement conditions, a mixture of the l-benzyl-3-ethyl-l,2-dihyd-roisoquinoline 110, a 3-substituted 1,2-dihydroisoquinoline that does not rearrange, and the l-ethyl-l,2-dihydroisoquinoline 111, which normally gives disproportionation, was treated with dilute acid. The 3,4-dihydroisoquino-linium salt 112 was obtained in 5% yield. This experiment demonstrated that the transfer of a benzyl group from a 1,2-dihydroisoquinoline (110), existing as a 1,4-dihydroisoquinolinium salt in acidic solution, to form the 3,4-dihydroisoquinolinium salt 112 is possible. The low yield of 112 can be... 

A completely different route devised by Prelog and co-workers (14) not only afforded a new synthesis of the erythrinane skeleton but also achieved a method of introducing an oxygen function at C-3, the site of the aliphatic methoxyl in the alkaloids. The synthesis is outlined in Fig. 5. The dihydroisoquinolinium salt XXXIV was prepared by Bischler-Napieralski ring closure of the lactam XXXIII. Hydrolysis of the vinyl chloride of XXXIV gave the methyl ketone XXXV. When this salt was made alkaline, addition of the carbanion from the acidic methyl to the C=N double bond created the spiro link. Sodium borohydride reduction of XXXVI gave a mixture of epimeric alcohols. One of them had an IR-spectrum identical with that of a transformation product (XXXVII) of erysonine (If) and on resolution w ith tartaric acid its (— )-enantiomer proved to be identical with XXXVII. 

A dramatic increase in catalyst efficiency is observed when the 3,3-disubsti-tuted dihydroisoquinolinium salt (8) is used in place of catalyst (9), thus eliminating the base-catalysed isomerization (Scheme 5.12). 

SCHEME 5.14 The 2-(2-bromoethyl)benzaldehyde method for forming dihydroisoquinolinium salts. 

With the first two entries in Table 5.1, using the structurally simplest amines 13 and 14, no asymmetric induction was observed, and it became clear that a conformationally more defined and rigid system was required to impart reasonable enantioselectivities. Both the camphor 20-, 21- and methyl 16-based systems gave low ees, although these are two of the more common systems upon which chiral auxiliaries have been based. The fenchyl derivative 19 is the most selective under these reaction conditions. However, the N-(isopinocampheyl) dihydroisoquinolinium salt 17, which is considerably less sterically hindered than the fenchyl, is almost as selective, giving a better yield and increased rate of reaction. 

After this early work in setting up the optimum reaction conditions, a further, more detailed, study of catalyst structure was instigated. A range of dihydroisoquinolinium salts containing alcohol, ether and acetal functionalities was tested [24]. 

SCHEME 5.15 Base-induced ring closure of hydroxy dihydroisoquinolinium salts to oxazolidines. 

Several aminoether-based dihydroisoquinolinium salts were produced, and they proved to be much more active than the related derivatives of the parent aminoalcohols, but again poor enantioselectivity was observed in the epoxidation of... 

This high degree of conformational rigidity may be absent from the dihydroisoquinolinium salt (17), derived from ( )-isopinocampheylamine (Fig. 5.7). In that case, rotation aroimd the bond between the nitrogen atom and the chiral unit would then result in both diastereotopic faces of the iminium moiety... 

The preparation of this new family of catalysts was achieved by starting from an enantiomerically pure primary amine and 2-[2-(bromomethyl)phenyl]-benzaldehyde (27) (Scheme 5.19). 2-[2-(Bromomethyl)phenyl]benzaldehyde was prepared from the corresponding dibenzoxepine (28), by treatment with molecular bromine in carbon tetrachloride under reflux, following a similar procedure already proven in the dihydroisoquinolinium salt series. The catalysts were synthesized in three steps starting from commercially available 2,2 -biphenyl dimethanol (29). 

TABLE 5.3 Catalytic asymmetric epoxidation mediated by the new dibenzo[c,c]azepinium salts (30 and 31) a comparison to the corresponding dihydroisoquinolinium salts (17 and 24) ... 

The effect of reaction solvent To determine if the electronic effect could enhance enantiomeric excess in the epoxidation reaction several other solvents were screened, using our three most effective dihydroisoquinolinium salt catalysts (24), (36) and (37) (Table 5.12) [46], TPPP was found to be insoluble in carbon tetrachloride, ethyl acetate and dimethoxyethane. In dimethylformamide, the TPPP dissolved, but no reaction occurred when employing catalyst (24). However, TPPP was soluble in 1,2-dichloroethane, and epoxidation reactions performed in this solvent gave almost identical results to those obtained with... 

The corresponding dihydroisoquinolinium salts, however, show less substrate dependency, and, to further explore these catalysts, we were interested to discover if the change in major enantiomer formed is also observed in the epoxidation of alkenes other than 1-phenylcyclohexene. Using the most selective dihydroisoquinolinium catalyst (36) from the above study, we were able to epoxidize several unfunctionalized alkenes in acetonitrile and chloroform solution (Table 5.14). Reactions were carried out at a temperature of —40 °C, with 10 mol% of the catalyst. 

The Mannich reaction has been reviewed comprehensively by Blicke (1942), Reichert (1959), Hell-mann and Opitz (1960), and Tramontini (1973). These reviews also include synthetic applications of Mannich bases. Mechanistic studies of the Mannich reaction have been reviewed by Thompson (1968). Some variants of the Mannich reaction have been covered as subtopics in other reviews for example. Layer (1963) and Harada (1970) have reviewed general additions of stabilized carbanions to imines, while Bdhme and Haake (1976) have reviewed similar additions to methyleneiminium salts. In more specific reviews, Pai and coworkers (1984) have summarized stabilized carbanion additions to 3,4-dihy-droisoquinolines and 3,4-dihydroisoquinolinium salts in connection with the total synthesis of protober-berines and phthalide isoquinolines, and Evans et al. (1982) " have analyzed the stereochemical aspects of ester enolate and silyl ketene acetal additions to imines. 

Preformed cyclic /V,A-dialkyliminium salts i.e. where a ring Joins the a-caibon and positively charged nitrogen) have been used in enolate condensation reactions. The number of examples, however, is rather limited, probably because of complications arising through abstraction of enolizable protons. A -Dehy-droindolizidinium salt (69) represents one of the few examples of an enolizable, cyclic A, -dialkylimi-nium salt known to react with an enolate (equation 8). The use of a soft zinc enolate in this reaction may be crucial. The relative stereochemistry of the resulting 3-amino ester (70) is undefined. /V-Alkyl-3,4-dihydroisoquinolinium salts e.g. 71), a class of nonenolizable, cyclic iminium salts, have had extensive applications in the total synthesis of protoberberine and phthalide isoquinoline alkaloids. A review by Pai and coworkers has covered much of this work. In a more recent application by Yamazaki and co-... 

Fluoride anion promoted cyclizations of benzylsilane dihydroisoquinolinium salts have been employed to form five- and six-membered azacyclic rings (Scheme 45). For example, CsF in either protic (EtOH-H2O) or aprotic (MeCN) solvents has been used to form the isoquinoline alkaloid (l)-xylopinine (121) from (118). Yields for this conversion in the range 25-70% have been obtained. - The A-arylisoqui-nolinium salt (119) is reported to cyclize under aprotic conditions only (Bu"4NF in refluxing THF) to give (122) in 60% yield. A betaine intermediate (120) has been proposed for these transformations. The conversion of this intermediate (R = Bn n = 0) to (122), formally a 5-endo-lrig cyclization, can then be formulated as a six-electron electrocyclization. Iminium ion-benzylsilane cyclizations have been accomplished, sometimes with greater efficiency, photochemically (see Section 4.4.3). 

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