From 2-Alkylated Indoles

Bergman and Carlson (5) reported the preparation of 2-hydroxy-3-methylcarbazole (83), the key compound for synthesis of pyranocarb-azole alkaloids and using aldehyde (81) alkylate 2-methylindole (80) at the 3-position (82). Use of 2,3 unsaturated ketones (84) and 2- 

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Lonza Cie191 has recently patented a selective O-alkylation reaction of an indole derivative starting not from hydroxy- but from trimethylsilyloxy-indole (124). 

Indole and alkyl-indoles (38) are protonated in position 3 by the action of strong mineral acids.198,197 The tendency of the enamine salts to assume the immonium structure is very general the salts of ethyl j3-aminoerotonate are derived from the imino form at the expense of the conjugation between the carbonyl group and the double bond.12,198... 

Most recently, Wagaw, Yang, and Buchwald published a full account of the synthesis of indoles using the palladium-catalyzed amination process [185]. From the standpoint of catalysis, new results included improved turnover numbers and rates when Xantphos was used as ligand. Moreover, this ligand allowed diarylation of the hydrazone, including a one-pot sequential diarylation to provide mixed diaryl hydrazones. A procedure for the alkylation of N-aryl hydrazones was also reported. These procedures allow the formation of N-aryl and N-alkyl indoles after subjecting the products to Fischer conditions for indole synthesis. 

As nitriles are generally readily available this is the main route to simple tetrazoles. More complicated ones are made by alkylation of the product of a cycloaddition. The tetrazole substitute for indomethacin that we mentioned in Chapter 43 is made by this approach. First, the nitrile is prepared from the indole. The 1,3-dipolar cycloaddition works well by the azide route we have just discussed, even though this nitrile will form an enoF rather easily. 

N-Alkylation of 3-aroylindole 97 carried out at 80 °C with alkyl halides from ethyl through -hexyl, gives mixtures of products 98 and 99 in yields of 41-90% (Equation 15) <1998JOC4510>. In addition to the expected N-alkylated indoles 98, a substantial fraction of the product was formed by additional replacement of the methoxy group by an alkoxy group. The reaction is very temperature dependent, since a decrease of only 5 °C completely suppresses the formation of the 0-alkylation products with the ethyl or -propyl halide. However, -hexyl bromide provided a 75% yield of hexyl ether 99 under these conditions. 

Replacement of the aminoalkyl substituent by an alkyl chain results in N-alkyl indoles (non-AAIs) (e.g., 41, Fig. 10). The SAR of cannabimimetic 2-methylindoles indicates that compounds with N-alkyl substituents from w-propyl to n-hexyl have good affinities for both CBi and (TT receptors with a preference for CB2. The in vivo potencies of these compounds were reported to be consistent with their receptor affinities (Huffmann et al. 1994 Wiley et al. 1998). 

Indole and the simple alkyl-indoles are colourless crystalline solids with a range of odours from naphthalene-like, in the case of indole itself, to faecal, in the case of skatole (3-methylindole). Many simple indoles are available commercially and all of these are produced by synthesis indole, for example, is made by the high-temperature vapour-phase cyclising dehydrogenation of 2-ethylaniline. Most indoles are quite stable in air with the exception of those which carry a simple alkyl group at C-2 2-methylindole autoxidises easily, even in a dark brown bottle. 

Autoxidation occurs readily with alkyl-indoles, thus, for example, 2,3-diethylindole gives an isolable 3-hydroperoxy-3//-indole. Generally, such processes give more complex product mixtures resulting from further breakdown of the initial hydroperoxide singlet oxygen also produces hydroperoxides, but by a different mechanism. If the indole carries a side-chain capable of trapping the indolenine by intramolecular nucleophilic addition, then tricyclic hydroperoxides can be isolated. ... 

A related sequence is involved in the lithium aluminium hydride reduction of indol-3-yl-carbinols (which can be obtained from the corresponding ketones using milder reducing agents), with formation of the alkyl-indole. This constitutes a useful synthesis of 3-alkyl-indoles. The one-pot conversion of 3-formylindole into 3-cyanomethylindole with a mixture of sodium cyanide and sodium borohydride probably involves a comparable elimination from the cyanohydrin, then reduction. ... 

Friedel—Crafts alkylation. Alkenes (styrenes and trisuhstituted alkenes) alkylate indoles at the 3-position in CH2CI2 containing 5 mol% of TfOH (or an Au(III) species). Benzyl trifluoromethyl carhinols are obtained from reaction of arenes with trifluoro-methyl epoxides. The direction of epoxide ring opening is determined by the electron-withdrawing trifluoromethyl group. ... 

The antidepressant Iprindole (43) is obviously made from an indole (44) by alkylation with (46). Fischer indole disconnection reveals available cyclic ketone (45) as the starting material. Disconnection of (46) is standard C-X work from Chapter 6. 

In 1960, Mold et al. (2592) reported the isolation and identification of the tricyclic A-heterocyclic 5H, QH-dipyrrolo[l,2-fl r,2 -(i]pyrazine-5,10-dione (pyrocoll) V (Figure XVlI.E-3) from CSC and demonstrated its relationship to its precursor in tobacco, the amino acid proline. Obviously, pyrocoll is not an aza-arene but an amide. Rodgman and Cook (3279) reported the identification of indole, carbazole, and several alkylated indoles and car-bazoles in CSC and confirmed the presence of 5H, QH-dipyrrolo[l,2-fl r,2 -(i]pyrazine-5,10-dione (pyrocoll) V described previously by Mold et al. (2592). Rodgman and Cook also assessed previously reported biological studies on indole, 3-methylindole (skatole), and carbazole None was reported to be tumorigenic in laboratory animals [Hartwell (1544), Shubik and Hartwell (3664)]. 

Light-induced electron transfer from an indole to an alkyl, vinyl, or aryl halide would be expected to yield a radical anion which can ionize by loss of halide ion. This would give a radical that can attack an indole and so lead to products of substitution. Examples of this reaction for all three categories of halide have been observed. Photolysis of an aqueous methanol solution of indole with methyl chloroacetate gives a mixture of all the possible isomers of methyl indolylacetate in low yield. The 4-substituted isomer is formed in greatest amount (6.2%) and the yields of the six other isomers vary from 0.24 to 2.55% [62]. Photolysis... 

For 3-MI (IV), structure V Is proposed as the major product of photooxldatlon In water. This structure, o-(N-formyl)amlno-acetophenone (molecular weight > 163), Is supported by the mass spectrum of the 3-MI product found In aqueous CRM-1 (120 [lOOZ], 92 [51%], 135 [45%], and 163 [16Z]), Spectra of the other product peaks suggest that they are analogous products (acylamlno derivatives) from the photooxldatlon of other alkylated Indoles,... 

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