The Bischler indole synthesis

The above product (24 g, 0.067 mol) was dissolved in 90 10 dioxane-water (300 ml) and sodium borohydride (92.5 g, 0.067 mol) was added. The mixture was refluxed for 4h. The cooled solution was poured into 0.1 N HCl (1.11). A solid precipitated and was collected by filtration, dried and recrystallized from ether hexane to give 6,7-dibromo-4-methoxyindole (18.5 g, 90%). 

Adachi. K, Sasakura and T, Sugasawa, Chem. Pharm. Bull. 33, 1826 (1985) K. Sasakura, M Adachi and T. Sugasawa, Synth. Cominun. 18, 265 (1988), 

There is an experimental variation in which an W-phenacylpyridinium salt is heated with an aniline[4]. This reaction can also be readily accommodated to the mechanism involving an imine intermediate. There are a few examples of use of other types of a-halokctoncs[5,6] but most of the synthetic applications have been to 2-arylindoles. 

Printed with FinePrint 2000 - register at http //wwwfineprint C( 

These two methods are closely related but differ in the point of initial attachment of the substituent from which the carbocyclic indole ring is constructed. One strategy for building up 2-substituted pyrroles capable of 

---

Aromatic amines react with 1-haloketones or 1-hydroxyketones to yield substituted indoles. This reaction is known as the Bischler indole synthesis (30). 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

The reaction of 7 -unsubstituted anilines with phenacyl halides is a useful way to make 2-arylindoles <7 JCS(C)2606>. This reaction is known as the Bischler indole synthesis. The reaction is typically carried out by heating a phenacyl halide with an excess of an anUinium salt. The reaction is believed to involve imine formation followed by protropic shifts and cyclization at the less hindered aldiminium carbon (Scheme 36) <80AJC343>. 

The Bischler-Mohlau indole synthesis, also known as the Bischler indole synthesis, is the formation of a 2-arylindole from an a-bromoacetophenone and excess aniline.Although not widely used in making indoles, one of the syntheses of fluvastatin sodium (Lescol) took advantage of the Bischler-Mohlau indole synthesis to assemble its indole core. As shown below, reaction of a-chloroketone with A-/-Pr-aniline at elevated temperature generated the tertiary amine. The resulting A-/-Pr-aniline underwent a ZnCb-mediated Bischler-Mohlau indole synthesis also at an elevated temperature to afford the indole core structure of fluvastatin. ... 

The Bischler-Mohlau indole synthesis, also known as the Bischler indole synthesis, refers to the synthesis of 3-arylindoles from the cyclization of ca-arylamino-ketones and excess anilines. 

Despite the vagaries of the mechanism, the Bischler indole synthesis is extremely useful, and several variations are known. Buu-Hoi and colleagues anployed a modified version of this indole synthesis to the preparation of 2-arylindoles [12] and polycyclic indoles [13] (Scheme 2, equation 2). Their modification was to heat the w-ary lamino ketone at 230-250 °C in inert silicone oil. Some indoles... 

For more than 30 years Black and his colleagues made extensive use of the Bischler indole synthesis [15-22]. Some of the highlights of this work are shown in Scheme 3. The conversion of 8 to indoles 9 demonstrates that even an... 

Scheme 3 Black and other Variations of the Bischler Indole Synthesis...

A wide range of applications of the Bischler indole synthesis is tabulated in Table 1 [28-32, 37-43]. In some... 

Some other modifications of the Bischler indole synthesis have been developed. One such modification is that of Moody and coworkers, who employed rhodium to effect N-H insertion of an a-diazo-p-ketoester to an aniline (Scheme 5, equations 1 and 2) [58-60]. The so-formed arylamino P-ketoester 16 was smoothly converted to indole 17 with the ion-exchange resin Amberlyst 15 or in somewhat lower yield with boron trifluoride etherate [59]. These workers extended the method to the synthesis of A-unsubstituted indoles using the novel A-protecting groups, A-(2-ethoxycarbonylethyl)... 

Table 2 Applications of the Bischler Indole Synthesis to Cryptolepine and Related Indoles...

---