Bischler-Napieralski reaction oxidation

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). 

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

N,N-Bisbromomagnesiumaniline, 33 Bischler-Napieralski reaction, 394 Bis(2-chloroethyl)ether, 142 Bischloromethylation, 84 Bis(chloromethyl) ether, 83 Bis-(1,5-cyclooctadiene)nickel(0), 33-35 Bis(dibutylacetoxytin)oxide, 393,394... 

F. Cularine.—New syntheses of ( )-cularine (ISO) and its derivatives using intramolecular Ullmann186 and phenolic oxidative coupling187,188 reactions as key steps have been reported. It is well known that 7,8-disubstituted isoquinolines cannot be prepared by the Bischler Napieralski reaction. This problem was circumvented (Scheme 14) by using an ethoxycarbonylamino-/ -phenethyl-amide (177) in order to activate the para-position and thus to effect the required cyclization reaction (177) — (178).186 Conventional steps then led to the phenol (179) which under Ullmann reaction conditions gave (+)-cularine (180). 

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). 

Kametani et al. (544,545) and other workers (546-561) endeavored to carry out the synthesis of cularine alkaloids by phenolic oxidation (bio-genetic type of synthesis) of the corresponding derivatives of laudanosine. The paper (549) describes the synthesis of these bases via the 6-ethoxycar-bamido-3,4-dihydroisoquinolines, which were converted to 6-amino-isoquinoline. By Ullmann reaction it gives the compound 52 and ( )-cularine (51) (Scheme 18). Cularine-type alkaloids were also synthesized by the intramolecular Ullmann reaction of 7,8-disubstituted isoquinoline obtained by the usual Bischler-Napieralski reaction from the phenolic bromoamide (pathway a) (544, 548). However, in the papers referred to (557,558,561), the rings A, C, and D were formed first (pathway b), and only then was the ring formed during the synthesis of cularine. 

Tryptamine cyclization can also be conducted at the amide oxidation level, which is an example of Bischler-Napieralski reaction. The usual reagent is POCI3, which generates a chloroiminium ion intermediate. The immediate products of cycUzatiOTi are iminium ions, which are typically then reduced. 

Norreticuline has also been synthesized by employing the Bischler-Napieralski reaction [B-HCl, mp 165°-166°J 110). The versatility of reticuline as a chemical intermediate in the production of other alkaloid structures is apparent from its controlled oxidation. When the racemic form was oxidized with manganese dioxide the dienone LIX, which is the racemic form of the alkaloid salutaridine is produced 111). The same results are obtained when the oxidation is carried out with potassium ferricyanide in aqueous solution containing sodium carbonate (— )-reticuline affords the natural ()-salutaridine (7). If the same oxidation agent is used at — 10° in ammonium acetate solution, ( + )-isoboldine (LX) is formed from racemic reticuline (112). 

Isolaudanosoline is the name given by Franck and Blaschke (196) to the tetraphenolic base CXXXIV (R = H). The tetramethyl derivative (CXXXIV R = CH3) [mp 76°-77° B HCI, 139°-141°] was prepared by Livshits et al. (197) who employed the Bischler-Napieralski reaction although they obtained instead of the usual dihydroisoquinoline base (CXXXV R = H2) the ketone CXXXV (R = O) whose methiodide on reduction afforded CXXXIV (R = CH3). In the absence of oxygen the dihydro base CXXXV (R = H2) can be prepared directly and its methiodide on reduction with sodium borohydride yields CXXXIV (R = CH3) [oil picrate, mp 189°]. When the methiodide of the latter base (CXXXVI R = CH3) was demethylated with hydrobromic acid the methobromide of isolaudanosoline was obtained (CXXXVI R = H). Its oxidation in aqueous solution with ferric chloride afforded an aporphine base (CXXXVII) [chloride, mp 225°-228° bromide, mp 170°-174°]... 

Problem 20.40 Outline a mechanism for the Bischler-Napieralski synthesis of 1-methylisoquinoline from N-acetylphenylcthylamine by reaction with strong acid and P,0, and then oxidation of the dihydroisoquinoline intermediate. 4... 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Bischler-Napieralski and Pictet Spengler reactions continue to serve well for benzylisoquinoline syntheses.76,77 In the latter reaction, use of a-formylphenyl-acetic esters for the non-nitrogen-containing component appears to be advantageous.77 An interesting sequence of reactions (43)—>—>(44) (Scheme 4) has apparently been applied to the synthesis of papaverine [44 R = 3,4-(MeO)2-C6H3CH2 ] and related alkaloids.78 An attempt to convert ( )-reticuline (37 R = H) into a morphinandienone-type alkaloid by enzymic oxidation with... 

F-L (Fig. 2). The Friedel-Crafts reaction (limited in the 1-benzazepine series), Dieckmann, acyloin, and aldol condensations, Bischler-Napieralski, Vilsmeyer, and Pictet-Spengler-type reactions, and phenolic oxidative... 

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