The Indoloquinazolines

Compound 52 was synthesized by condensation of tryptanthrin (53) with N-acetylindoxyl followed by mild hydrolysis. Candidine was briefly described in 1922 by Martinet and Grosjean as a condensation product of indoxyl and tryptanthrin. 

This compound has been known since 1892 and was previously synthesized in 1915 by oxidation of isatin with neutral potassium permanganate 134). Bird 135) has synthesized 53 from 0-methylisatin and o-aminobenzaldehyde. The isatin-a-(2-formylanil) 54 (appears to exist predominantly as 55) was converted to 53 by oxidation with CrO. The reaction of 7 l-sodioi satin with o-nitrobenzoyl chloride gave l-(2 -nitrobenzoyl)isatin, and its reduction afforded 53 (756). Bergman et al. 126,153) have developed a simple method heating of isatin, isatoic anhydride, and diisopropyl carbodiimide in pyridine with A-meth-ylpiperidine as catalyst afforded 53 in high yield. For information on other 

Chemical Shifts (t) and Coupling Constants (J Hz) for Protons on C-I-C-4 and C-7-C-10 of Tryptanthrin 

---

An analog of compounds 152 — the indoloquinazoline derivative 153 — was obtained with a 23% yield by boiling 7-chloroisatoic anhydride with isatin in pyridine [88],... 

It has been shown that a mixture of an indoloquinazoline and anthranilic acid, adsorbed on graphite, led to cydization in good yields after 30 min at 140 °C, in less time than for the purely thermal procedure under similar conditions, when a very poor yield is obtained even after 24 h [63],... 

One example of a spiro-4,5-dihydro-l,2,4-oxadiazole has appeared, whereby the spiro[indoloquinazoline]-4,5-dihydro-l,2,4-oxadiazoles 337 were prepared in good yields from the imines 336 (Equation 69) <2005SC765>. 

A mixture of indoloquinazoline 593 and excess of anthranilic acids adsorbed on graphite led to the cyclized compound 594 in 80-90% yields within 30 min. Under... 

Yamazaki, M., A. Ikuta, T. Mori, and T. Kawana Biosynthesis of Evodia Alkaloids. II. The Participation of Ci-Unit to the Formation of Indoloquinazoline Alkaloids. Tetrahedron Lett. 1967, 3317. 

Members of the family contain alkaloids based on several major pathways such as benzylisoquinoline (tyrosine derived), quinolone, furoquinoline, quinazoline (all from anthranilic acid), imidazole (histidine), indoloquinazoline (tryptophan), and both simple aliphatic and aromatic amines. In the tribe Ruteae (Rutoideae), no fewer than five types of alkaloids are common to the three major genera. Quinolone, furoquinoline, and acridone alkaloids are especially widespread within the family, being found in four of the five... 

Since Watanabe s synthesis of 4(3H)-quinazolinones in 1993 via transition-metal catalyzed reductive N-heterocychzation [ 181 ], several catalytic methods for quinazoline synthesis have been developed [182-186]. For example, palladium-catalyzed cyclocarbonylations of halides with appropriate reactants provided regioselective synthesis of 4(3H)-quinazolinone derivatives [182] and indoloquinazolines [184]. Also selenium-catalyzed reductive N-heterocyclization to quinazolinones has been developed by Sonoda et al. [183]. Copper-catalyzed heteroannulation with alkynes has been developed as highly region- and stereoselective route to 2-(2-arylvinyl)-l,2,3,4-tetrahydroquinazolin-4-ones 64 by Kimdu et al. [ 185] (Scheme 12). Recently, condensation of anthranylamide with various aldehydes to 4-quinazotinones has been found to give excellent yields in the presence of cupric chloride [186]. 

Perhaps the greatest value of the Sandmeyer synthesis is the preparation of isatin scaffolds for the generation of compounds of medicinal interest. The ambiphilic nature of isatin allows it to undergo ring forming reactions to produce a variety of heterocyclic systems. Reaction of isatin 33 with substituted isatoicanhydrides 34 to form indoloquinazoline 35,serves as an example. 

Adams M, Mahringer A, Kunert O, Fricker G, Efferth T, Bauer R (2007) Cytotoxicity and P-glycoprotein modulating effects of quinolones and indoloquinazolines from the Chinese Herb Evodia rutaecarpa. Plant Med 73 1554—1557... 

Kobayashi Y, Nakano Y, Hoshikuma K, Yokoo Y, Kamiya T (2000) The bronchocon-strictive action of evodiamine, an indoloquinazoline alkaloid isolated from the fruits of Evodia rutaecarpa, on guinea-pig isolated bronchus possible involvement on vanilloid receptors. Planta Med 66(6) 526-530. doi 10.1055/s-2000-8615... 

---