Fused indole

A remarkably simple fused indole devoid of the traditional side chains is described as an antidepressant agent. Michael addition of the anion from indole ester 119 to acrylonitrile affords the cyanide 120. Selective... 

Fused indoles, as shown in Eq 10 64, are also prepared by this method... 

Flynn et al., also described the synthesis of the fused indoles [73]. The o-iodotrifluoroacetanilide 110 was coupled to aryl alkyne 111 under Sono-gashira conditions followed by subsequent reaction with aryl iodide, 107 with gaseous carbon dioxide produced the fused indole 158. Lewis acid dealkylation with aluminum trichloride produced the deprotected alcohol 159. 

Several investigators have developed the reductive cyclization of o-nitrostyrenes into an efficient synthesis of indoles. Thus, research by the groups of Watanabe [458, 459], Sbderberg [460, 461], and Cenini [462, 463] have established this reductive Pd-catalyzed AMieteroannulation reaction as a viable route to simple indoles and fused indoles (372) as shown below. Ohta... 

In conclusion, the fantastically diverse chemistry of indole has been significantly enriched by palladium-catalyzed reactions. The accessibility of all of the possible halogenated indoles and several indolyl triflates has resulted in a wealth of synthetic applications as witnessed by the length of this chapter. In addition to the standard Pd-catalyzed reactions such as Negishi, Suzuki, Heck, Stille and Sonogashira, which have had great success in indole chemistry, oxidative coupling and cyclization are powerful routes to a variety of carbazoles, carbolines, indolocarbazoles, and other fused indoles. 

A one-step method has been developed for elaboration of fused indole 87 via a palladium-catalyzed intramolecular indolization of 2-chloroaniline 86 bearing tethered acetylene (Equation (11) (2006OL3573)). 

Two types of benzothiazepines with fused indole rings 301 and 302 (Figure 4) have been reported as products of a Fischer indole type synthesis (1993EJM659). 

A fused tricyclic ring system based on an indole provides yet another NSAID. Michael addition of the anion from diethyl methylmalonate to cyclohexanone followed by acid hydrolysis of the product gives cyclohexanone (21-3), which incorporates the characteristic profen 2-substituted carboxylic side chain. Sequential reaction with para-chlorophenylhydrazine and a strong acid gives the fused indole... 

Diaryliodonium fluorides can be used as efficient reagents for the arylation of silyl enol ethers [71, 72]. The reaction of silyl enol ethers 95 with o-nitro-phenyliodonium fluoride 96 results in a regiospecific arylation yielding arylke-tones 97 in good yields (Scheme 43) [72]. This arylation has been applied in a new, regiocontrolled synthesis of carbocycle-fused indoles [72]. 

Examples of the syntheses of fused indoles by the SRN1 mechanism are depicted in Scheme 10.45. The photoinduced reactions of 22 with the enolate anions of cyclic ketones afford the corresponding indoles from moderate to good yields [61],... 

Barolo, S.M., Lukach, A.E. and Rossi, R.A. (2003) Syntheses of 2-substituted indoles and fused indoles by photostimulated reactions of o-iodoanilines with carbanions by the SRN1 mechanism. Journal of Organic Chemistry, 68, 2807—2811. 

Substrate 16 reacts under irradiation in DMSO with the enolate anions of 1-indanone (n= 1), 1-tetralone (n = 2), and 6,7,8,9-tetrahydro-benzocyclohepten-5-one (n = 3) to afford fused indoles (Sch. 21) [92]. 

In the first reported syntheses <92T1039> of either of the fused indole heterocycles shown in Equation (26), dihydropyrano[3,2-ej- and [2,3-/]indoles (53) and (54) were prepared from a mixture of nitrodihydrobenzopyrans via condensation with DMFDMA (DMF dimethyl acetal) followed by reductive cyclization of the resulting /f-aminostyrene derivatives. The isomers were separated by flash chromatography. 

The fused indoles 91 (n = 1-3) have been synthesized by Stille coupling of the stannylbenzene 92 with 2-iodo-2-enones 93, followed by intramolecular palladium-catalyzed... 

A Suzuki coupling of 5-chloro-2-methyl-6-phenyl-2H-pyridazin-3-one (10) ultimately led to diazino-fused indole 11 and cinnoline 12 and allowed access to a novel pyrimidoisoquinoline ring system in a one-pot fashion <02T10137>. Mn(II)-azido networks of the type [Mn(N3)2(L)] like 13 with new 3-D topologies were obtained using both pyridazine and pyrimidine ligands <02CC64>. 

Diaryliodonium fluorides (Ar2IF) are effective reagents in arylation of silyl enolates.330 They have been used for the regiocontrolled synthesis of carbocycle-fused indoles (Scheme 26).331 Ph4BiF also serves for efficient regioselec-tive cr-phenylation of carbonyl compounds via silyl enolates.332 This approach can be extended to cr-alkenylation of carbonyl compounds. 

C-Alkylation of pyrroles and indoles can be mediated by alumina in association with the appropriate halide. 3-Indolyl sugar derivatives have been obtained by alkylation reactions of indolylmagnesium bromide. This type of alkylation has been extended to ring-fused indoles 105 and yields 3//-indole derivatives 106 in good yields. 

Isatins have been used for the synthesis of fused indole derivatives. The reduction of l-methylisatin-3-oximes, by Zn in acidic media, leads to an acetamidooxindole, which upon reaction with P4S10 gives indolothiazoles in moderate to good yields (Scheme 36). 

Reaction of enaminones and carboxylic acids is mainly interesting as a route for cyclization of suitable substituted enaminoketones to N-heterocycles45. In this way iV-cyclohexenylglycines can cyclize to indoxyl derivatives (equation 30). By a similar intramolecular acylation at the / -carbon of enaminones, fused indoles or pyrrole derivatives are obtained46-48. 

Benzynes are also involved in a route to indoles illustrated by conversion of the imine 221 into the indole 222, which proceeds via the intermediate 223 (Scheme 25). This methodology is also useful for synthesis of fused indole derivatives <2003S1661>. 

Indoles have also been accessed by annulation of cyclic ketones with t>-chloroaniline derivatives, as illustrated by the transformation of the precursor 386 to the functionalized tetrahydrocarbazole 387 (Equation 110) <2004AGE4526>. Similar palladium-catalyzed annulations involving t>-iodoanilines and ketones leading mainly to fused indoles have been described previously <1997JOC2676>. 

It has also been demonstrated that carbanions may react with o-iodoaniline under irradiation to give indoles. This approach has for instance been used for the constmction of the fused indole 400 (Equation 113) <2003JOC2807>. 

Cyclopentenones-fused indoles and quinolines can be prepared via intramolecular amiulations (Scheme 263). ... 

Irradiation of the vinylic pyrroles 71 in benzene or methanol produced the ring systems 72 in low yields via the non-isolable intermediates 73. Subsequent hydrolysis of the carbamate under basic conditions gave the parent fused p3rrole <03JOC7524>. Related photochemistry involving stilbenyl pyrroles was investigated for the preparation of fused indole and isoindole derivatives <03TL7337>. 

Reaction of o-iodoaniline 84 with carbanions under irradiation produced several 2-substituted indoles 85, or various fused indolic systems in moderate yields. The events leading to this outcome featured a C-C bond formation via the SrnI mechanism <03JOC2807>. 

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