7-Cyanomethylated indole

In contrast, reaction of 82 with NaCN in DMF-H2O at reflux results in the formation of 7-cyano-6-nitroindole (201, 15%) and 83 (4%) as isolable products together with tar matter, and, to our surprise, 2- and/or 3-cyano-6-nitroindoles are not detected at all. When the reaction is carried out in DMSO at 150°C, only demethoxylation occurred to give 83 (62%). On the other hand, utilizing KOt-Bu and p-chlorophenoxyacetonitrile (25), the vicarious substitution reaction (87ACR282) of 82 proceeds smoothly to give a 7-cyanomethylated indole (202, 67%) (2001H1151). 

SYNS 3-(CYANOMETHYL)INDOLE 3-IN DOL-ACETONITRILE INDOLEACETONITRILE INDOLE-3-ACETONITRILE lH-INDOLE-3-ACETONITRILE INDOLYLACETONITRILE USAF CB-29... 

CYANOMETHYL)INDOLE see ICWOOO CYANO(METHYLMERCURI)GUANIDINE see MLF250 CYANON S see EHP700... 

Matsumoto, M., Watanabe, N., and Ishida, Y, A facile synthesis of 4-(cyanomethyl)indoles and 4-(ethoxycarbonylmethyl)indoles from 5-halo-4-oxo-4,5,6,7-tetrahydroindolcs, Heterocycles, 24, 3157, 1986. 

Fig. 6. Base-catalyzed formation of a peroxy intermediate from cyanomethyl indole.

Dimethylindole magnesium iodide reacts with chloroacetonitrile in ether to give 3-cyanomethyl-2,3-dimethylindolenine (234). Majima and Hoshino obtained 3-(2-cyanoethyl)lndole (235) by the action of -chloropropionitrile on indole magnesium iodide. The reaction was slower with -chloropropionitrilc than with chloro-aoetonitrile. 3-(3-Cyano-w-propyl)indole (236), required as an intermediate in the synthesis of 3-indolyl-y-w-butyric acid, was prepared, but not isolated, by the action of y-chloro-w-butyronitrile on indole magnesium iodide. ... 

The cyanomethylation of nitroarenes followed by alkylation and reductive cyclization yields indoles (see Chapter 9, which discusses the VNS reactions) (Eq. 10.56).74... 

TV-Acetyl indolin-3-one 123 was converted to 3-cyanomethyl-3-(l,l-dimethylallyl) indol-2-one, 127, by a successive isomerization-Claisen rearrangement sequence (equation 63)91.7V-Acetylindolin-3-one 123 was converted in two steps to a mixture of E- and Z-isomers of 124. Isomerization of both isomers of 124 to 125 was accomplished with DBU. Claisen rearrangement of 125 afforded a 13% yield of 126, which was subsequently deprotected to give 3-cyanomethyl-3-(l,l-dimethylallyl)indol-2-one, 127, in 47% yield. 

The synthetic utility of many of the substitution reactions described so far is limited because there are well-established thermal routes to the same products. However, a third group of photochemical nucleophilic substitutions involves aryl halides and nucleophiles based on sulfur, phosphorus or, of particular importance, carbon. Two examples are the reaction of bromobenzene with the anion of t-butyl methyl ketone 13.12), and the replacement of bromine by cyanomethyl in 2-bromopyridine (3.13). This type of reaction offers a clear advantage over lengthy thermal alternatives, and intramolecular versions have been used in the synthesis of indoles (e.g. 3.14) or benzofurans from o-iodoaniline or o-iodoanisole respectively. 

JV,A-E)imethyl-2-[5-(cyanomethyl)-1 H-indol-3-yl] ethyl amine 4% H2S04 76 [7]... 

The cyclization of 4-cyanomethyl or 4-carbethoxymethyl-substituted 3-indolylpropionic acids 187 by the action of sodium hydride in tetrahy-drofuran leads to 5-substituted l,3,5-trihydrobenzo[c[Pg.35]

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

Ethyl 4-methyl-7-azaindole-3-acetate (155, R = H), obtained from the attempted cyanomethylation of the indole, was hydrolyzed to the 3-acetic acid (156, R = H) (54%), which was treated in succession by thionyl chloride and ammonia to give the 3-acetamide (157) (78%). Reduction with lithium aluminium hydride gave the azatryptamine (150, R = R = R" = H) in 94% yield. The 6-chloro ester (155, R = Cl) was hydrolyzed also to the acid (156, R = Cl.) ... 

---