Indole Bischler synthesis

Like the venerable Fischer, Madelung, and Nenitzescu indole syntheses, the Bischler indolization has stood the test of time and continnes to find utihty in indole synthesis. This method, which is also known as the Bischler-Mohlau indole synthesis, was discovered by both of these German chemists within the span of a decade [1 ]. Other early pioneers 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

The mechanism is discussed in more detail later in this chapter. An early example of the Bischler indolization is that of Blackball and Thomson (equation 3) [11]. 

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

S-COgMe, S.S-MeOg Ar= Ph, 4-MePh, 4-CIPh, 4-FPh, 4-MeOPh, 3-MeOPh, 2-MeOPh, 4-N02Ph, 2-BrPh, 2-thienyl, 2-furyl, 2-naphthyl (indole numbering) 

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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. ... 

Mdhlau-Bischler Indole Synthesis, Mohlau-Bischler Synthesis)... 

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. 

Example 5, Microwave-assisted, solvent-free Bischler indole synthesis... 

Wender and White published a very simple indole ring synthesis that involves the generation of a bis-lithio anion 1 and its reaction with an a-halo carbonyl compound 2, followed by acid- or base-catalyzed dehydration [1,2], The overall transformation is shown in Scheme 1, along with three examples. This chemistry illustrates yet another indole ring synthesis that uses a-halo carbonyl compounds [3]. We will encounter these compounds again with the venerable Bischler indole synthesis in Chapter 23. A summary of several Wender indole ring syntheses is tabulated in Table 1 [1, 2, 4-7], Entry 5 features a directed lithiation method to the bis-lithio nucleophile [5], a modification also described by Wender and White [2], Sainsbury and... 

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... 

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...

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