Isoquinoline lactams

Nonsensitized photochemical oxidation of dihydrodibenzo[a,5 ]quinolizinium compounds such as berberine (102) in the presence of nucleophilic reagents affords isoquinoline lactam aldehydes (103) (Scheme 13) <84H(22)10l>. A mechanistic proposal <81H(16)1735> involving the intermediacy of the dihydroberberine (104) was rejected on the basis of the results of direct irradiation of this compound. Participation of singlet oxygen was also excluded. 

A novel route to isoquinoline derivatives involves irradiation of an N-chloroacetylbenzylamine to afford an isoquinoline lactam. ... 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

When discussing seco alkaloids the question of their genesis should not be disregarded. Are they true alkaloids or artifacts of isolation It is difficult to answer this question with certainty. Some of them, e.g., secophthalide-isoquinoline ene lactams, are postulated to be formed during the extraction process however, most of them are believed to be metabolites produced naturally. This may be evidenced by the fact that some of these alkaloids retain optical activity, and in addition many of them can be synthesized in biomimetic syntheses in the laboratory. Thus, one can generalize the opinion of Shamma (10), whose significant contribution to the field of secoisoquinoline alkaloids should be acknowledged, that [a process]. .. could presumably occur in vivo at least as readily as it could in vitro. ... 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Laterally lithiated tertiary amides are more prone to self-condensation than the anions of secondary amides, so they are best lithiated at low temperature (—78 °C). N,N-Dimethyl, diethyl (495) and diisopropyl amides have all been laterally lithiated with aUcyllithiums or LDA, but, as discussed in Section I.B.l.a, these functional groups are resistant to manipulation other than by intramolecular attack" . Clark has used the addition of a laterally lithiated tertiary amide 496 to an imine to generate an amino-amide 497 product whose cyclization to lactams such as 498 is a useful (if rather low-yielding) way of building up isoquinoline portions of alkaloid structures (Scheme 194) ". The addition of laterally lithiated amines to imines needs careful control as it may be reversible at higher temperatures. ... 

Pyridoazepinium salts 307 and 308 are cleaved by base to yield pyridoyl-butadienes 312 and 311, respectively (82JOC2792). The relevant reactions of pyridoazepinone 288 and its benzolog 290 (Scheme 90) involve the cleavage of the lactam bonds and subsequent rearomatization to form pyridines and isoquinolines, respectively (91HCA1095, 93H(35)817). 

Hence, lithium salt 343a is trapped by aldehydes, and subsequent intramolecular attack of the intermediate alkoxide on the lactam moiety leads to pyridinophanes 405a and b. Ethanolysis of lactam 288 under acidic or basic conditions, even at —78°C, affords ester 406, whereas the reactions of lactams 288 and 290 with 4-methyl-l,2,4-triazoledione (MXAD) give mixtures of cycloadducts 407a and b or the respective isoquinolines. Tricyclic 290 when irradiated suffers loss of carbon monoxide to form butadiene 408. 

The natural Aristolochia N-containing substances may be divided into three structural types nitrophenanthrenic acids, phenanthrene lactams, and isoquinoline alkaloids. 

Of the lactam derivatives of quinoline and isoquinoline, 2(1 H)-quinolinones and 1 (2//)-isoquinolinones (carbostyrils and isocarbostyrils) have long been known. Although over 100 years have passed since Gabriel discussed the tautomerism of 3(2//)-isoquinolinone derivatives (1) (3-isoquinolones, 3-hydroxyisoquinolines or 3-isoquinolinols), these com-... 

Bose reported the dehalo genation of bromoanthracene, bromonaphthalene and several bromobenzenes under microwave-assisted hydrogen transfer conditions (ammonium formate, 10% Pd/C, ethylene glycol). An application of this reaction is the synthesis of several (3-lactams and isoquinoline derivatives14. 

Two mechanisms (i.e. direct hydrolysis and alternatively a path via an unstable acyl phosphate intermediate) are involved in the hydrolysis in phosphate buffer of N-arylsulfonyl / -lactams such as (130).107 The acyl phosphate intermediate can be trapped with hydrazine. The alkaline hydrolysis of some torsionally distorted lactams, i.e. the bridged benz[rfe]isoquinolin-l-ones (131), in 70% (v/v) DMSO-water has been compared under the same conditions with the hydrolysis of AvA-dimethyl-1 -naphthamide (132). The relative rates of reaction and activation parameters indicate the effect of torsional distortion.108 The reaction of the tricyclic azetidinones (133) with trifluoroacetic acid gives the bicyclic thioesters (135). The mechanism may involve acid-catalysed elimination of methanethiol to give an azetinone intermediate (134) which, after nucleophilic attack of the thiol, is converted into (135).109... 

Pictet-Spengler isoquinoline synthesis. The final steps in a synthesis of (—)-antirhine (2), a Corynanthe-type indole alkaloid, involved partial reduction of the lactam 1 to a hemiamina), which cyclizes to 2 in the presence of dilute HC1,2... 

Nagarajan, M. Xiao, X. Antony, S. Kohlha-gen, G. Pommier, Y. Cushman, M. Design, synthesis, and biological evaluation of indeno-isoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen./. Med. Chem. 2003, 46, 5712-5724. 

Lactams, e.g. (26) (67T681), can be chlorinated in the usual manner with phosphorus oxychloride. Phenylphosphonic dichloride is often a preferable reagent in this type of reaction, especially if the reaction requires a relatively high temperature for complete conversion, e.g. for the isoquinoline analogue (27) (75JCS(P1)2190). 

In the alkylation of lactams the choice of conditions and reagents is important for controlling the reaction towards N- or O-alkylation. Methylation of the isoquinoline... 

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