Indoles 4- substituted, preparation

The reaction between zinc-copper reagents and acid chlorides is very general and provides a useful synthesis of ketones [7, 34, 41, 42], This acylation has also been used to prepare various indoles substituted in position 2 (Scheme 2.42) [88],... 

A variety of syntheses are used to prepare indoles the most versatile for indoles substituted in the benzene ring is still the venerable Fischer indolization process. 

R Cl) and the hydroxyindolinones (147 R H) and (147 R Cl). The phenylazoindole (148) forms the ipso-substitution product (149) on nitration similarly, 3-hydroxymethyl-l-methyl-2-phenylindole (150) affords the azocompound (148) on treatment with benzenediazonium salts.The 3H-indole (151), prepared by the action of <>-nitropheny1sulpheny1 chloride on 2,3-dimethylindole, rearranges to the indole (152) at 95 °C. Carbon monoxide reacts with IJ-acyl-indoles in the presence of palladium(II) acetate and sodium peroxydisulphate, Na2S2°8 to N- Undole-3-carboxylie acids.The iminoindoline (153)... 

Sestelo and Sarandeses generated tris(indol-2-yl)indium 49 for use in palladium-catalyzed cross-coupling reactions (Scheme 9) [227]. Lithiation of 4 with n-butyllithium followed by treatment with indium trichloride gave 49 which was used directly in palladium-catalyzed cross-coupling reactions leading to 2-arylin-doles 50. These same authors exploited this chemistry to prepare indole-substituted maleimides [228]. 

Although a variety of synthetic methods have been used to prepare indoles many of these lack generality and are somewhat restrictive since they employ conditions, e.g., acid or strongly basic cyclizations or thermal decarboxylations, which are too harsh for labile substituents. This efficient, two-step procedure illustrates a general, simple, and convenient process for preparing a variety of Indoles substituted in the carbocyclic ring, as can be seen In Table I. Since many of these examples served to determine the scope of this method, the yields in most cases have not been optimized. In many cases, the starting materials are readily available or can be easily prepared. 

Various 4-substituted indoles were prepared and a synthetic method for 4-nitro-l,3,4,5-tetrahydrobenz[cd]-indole derivatives was carried out [46] and also for 4,5-disubstituted lH-l,3,4,5-tetrahydrobenz[cd]indole derivatives [47] using intramolecular Michael addition. Furthermore, a method [48] was published describing the successful syntheses of 4-nitro-l,3,4,5-tetrahydro-benz[cd] indole and its 1-hydroxy derivative. 

Du Prez and coworkers presented a relevant approach concerning TAD-based chemistry described as a novel click and trans-click strategy (Figure 1.17a). ° The reaction of 4-butyl-l,2,4-triazoline-3,5-dione (BuTAD) with 2,4-hexadiene-l-ol (HDEO) yielded the Diels-Alder adduct TAD-HDEO in an extremely fast, traceless, and irreversible manner. The occurrence of a retro-Diels-Alder reaction can be excluded based on reference experiments with competing 2,4-hexadiene-l,6-diol. Furthermore, an addition-type adduct (TAD-indole) was prepared using a substituted indole, e.g., tryptophan in proteins. To demonstrate the trans-click reactivity. 

Using a similar procedure, they extend this methodology to the preparation of indoloazepinones 144. Interestingly, contrary to pyrrole-substituted alkynes 141, no rearrangement of the amide substituent was observed on indole-substituted alkynes 143 (Scheme 12.63) [67]. 

Liotta and Traynelis and coworkers prepared a wide range of indole-substituted 3-hydroxy-3-pyrrohn-2-ones (Scheme 106 2014JMC2334). For example, treatment of pyruvate 400, benzaldehyde (401), and trypt-amine (402) with pyridinium p-toluenesulfonate (PPTS) gives the 3-hydroxy-3-pyrroHn-2-one 403. 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

One type of o-aminobenzyl anion synthon is a mixed Cu/Zn reagent which can be prepared from o-toluidines by / i.s-trimethylsilylation on nitrogen, benzylic bromination and reaction with Zn and CuCN[l]. Reaction of these reagents with acyl halides gives 2-substituted indoles. 

A more highly substituted analogue was successfully used in the preparation of the penitrem class of terpenoid indoles[3]. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

Indol-2-ylcopper reagents can also be prepared from 2-lithioindoles and they have some potential for the preparation of 2-substituted indoles. 1-Methyl-indol-2-ylcopper can be prepared by reaction of 2-lithio-l-methylindole with CuBr[10]. It reacts with aryl iodides to give 2-aryl-1-methylindoles. Mixed cyanocuprate reagents can be prepared using CuCN[ll], The cyan-ocuprate from 1-methylindole reacts with allyl bromide to give 2-allyl-l-methylindole. 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline... 

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