Bischler-Napieralski cyclodehydration

Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the <5-lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the... 

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

Bischler-Napieralski cyclodehydration of amides.1 This reaction is traditionally effected with P205 or ZnCl2. It can also be effected under neutral conditions with (C6H5)3P and CCU (equation I). 

Application of the Bischler-Napieralski reaction to amides of tryptophan has been investigated. The cyclodehydration of acetyltrypto-phan under conventional conditions proved unsuccessful. Attempted ring closure of acetyltryptophan or its ethyl ester was accompanied by decarboxylation and aromatization, yielding... 

Among the many applications of cyclodehydration to the formation of heterocyclic systems is the Bischler-Napieralski reaction. In this reaction, amides of the type 35 are cyclized with phosphorous oxychloride ... 

Bischler-Napieralski Reaction. This synthetic method involves (he cyclodehydration of 4/-acyl derivatives of /t-phenethylamines to 3,4-dihyriroisoi uiiiolmrs. such as 1-methyl-3.4-dihydroisoquinoline. 

Starting from resin-bound N-acylated dipeptides 11 having tryptophan or a tryptophan analog as the C-terminal amino acid, a mixture-based combinatorial library of 46,750 indolepyridoimidazoles 12 was synthesized by double cyclodehydration under Bischler-Napieralski conditions (POCl3, dioxane, 100°) (Fig. 4).23 Twenty-two tryptophan analogs, 25 amino acids, and 85 carboxylic acids were used for the library synthesis. 

The carbonyl unit involved in the cyclization process is not restricted to aldehydes and ketones. The carbonyl of acid derivatives, such as amides can also be utilized. One of the more important cyclodehydration reactions is applied to the formation of heterocychc systems via cyclization of p-aryl amides, in what is called the Bischler-Napieralski reaction In this reaction amides of the type 47 are... 

Nagubandi, S., Fodor, G. Novel condensing agents for Bischler-Napieralski type cyclodehydration. Heterocycles 1981, 15,165-177. 

Cyclodehydration. Attempts to cyclize the imide (1) with phosphoryl chloride, the usual reagent for Bischler-Napieralski ring closure, gave back only starting material, but the lactam (2) was obtained by refluxing (1) with P2O., in xylene. ... 

Reagent for cyclodehydration. A Japanese groups prepared PPE as above and used the chloroform solution as such and found it to be an excellent reagent for the Bischler-Napieralski reaction. Thus phenylethylamides (I) are cyclized smoothly to dihydroisoquinolines (2) by refluxing with PPE in chloroform. Phenylpropylamides (3) similarly yield 3.4-dihydro-5H-2-benzopines (4). The same workers report that... 

Bischler-Napieralski reaction. Cyclodehydration of (i-phcncthylamidcs to 3,4-dihydroisoqui-nohne derivatives by means of condensing agents such as phosphorus pentoxide or zinc chloride. 

Intramolecular acylations of the Bischler-Napieralski type have been used as crucial steps in the synthesis of indole alkaloids of the yohimbine class <94JCS(Pl)299, 94TL1071>. Also, the aluminum chloride-catalysed reaction of the indolosuccinic anhydride (46) gave the bridged cyclic product (47) rather than the cyclopentanone (49), presiunably because the reaction involves initial acylation at C-3 and reaction via the less strained intermediate is favored. Formation of the cyclopentanone (49) can be achieved using the polyphosphate ester cyclodehydration of the modified intermediate (48) (Scheme 13) <90JCS(Pi)2487>. 

Many biologically active derivatives are based on the dihydrobenzodiazepine structure. The tranquilizer medazepam is of this type its synthesis (Scheme 9.56) is of interest because of its close resemblance to the Bischler-Napieralski isoquinoline synthesis, in that an amide is subjected to cyclodehydration with PPA. Here, a second nitrogen atom must be present in the side chain, as in the starting amide 9.114. This product is the tranquilizer medazepam (9.115). 

Cyclodehydrations. The Pictet-Gams modification of the Bischler-Napieralski reaction is an important method for the preparation of isoquinolines. This reaction relies on the dehydration of molecules such as (2) with P2O5 at high temperature... 

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