Indole derivatives synthesis

Tsuda, Y., Ishiura, A., Hosoi, S., and Isobe, K., Studies toward total synthesis of non-aromatic Erythrina alkaloids. Part 2. A general method for synthesis of perhydro-6/7-pyrido[2,l-z]indole derivatives. Synthesis of isoerythroidine skeleton, Chem. Pharm. Bull., 40, 1697, 1992. 

Blechert S, Knier R et al (1995) Domino reactions - new concepts in the synthesis of indole alkaloids and other polycyclic indole derivatives. Synthesis 592-604... 

Additionally, the intramolecular cyclization of 2-halo-AT-allylanilines provides optional proeedures for indole derivative synthesis. Many transition metal eatalysts have been developed in this field, such as cobalt, nickel and palladium, but stoichiometric amounts of catalysts are needed. In 1987, a eatalytie version was developed by Laroek and Babu. In the pres-enee of a eatal54ie amount of Pd(OAe)2, indoles, indolines, oxindoles, qui-nolones, isoquinolines and isoquinolones were formed in high yields in short reaetion times under mild temperatures (Seheme 2.106). 

Scheme 8.20 Polysubstituted indole derivatives synthesis via three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin.

Scheme 4.25 Indole derivatives synthesis via iron-catalyzed intramolecular CDC reaction.

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

Phenylhydrazine has been used in the synthesis of indole derivatives. The hydrazones of aldehydes and ketones contain-... 

The Batcho-Leimgruber indole synthesis involves the condensation of o-nitrotoluene derivatives 1 with formamide acetals 2, followed by reduction of the trans-p-dimethylamino-2-nitrostyrene 3 which results to furnish indole derivatives represented by... 

Ganellin and Ridley subsequently showed that this reaction was of wide applicability and could be applied to the synthesis of tryptamine (23) itself and a number of indole derivatives with 3-(S-mono- or 3- -dialkylaminoalkyl side chains where the side chain contained two or more carbon atoms.A number of compounds of this general type including 79, 80, 81, 82, 83, 84, 85, and 86 have been prepared by these authors. Trace quantities of the corresponding l-(/8-dialkylaminoethyl)indole derivatives were formed atthe same time as other isomers. However, only the A-substituted product. 

At the present time we have not attempted to isolate a-thioisatin, the presumed intermediate in the synthesis of indigo. However, it is immediately apparent that if this intermediate could be isolated or intercepted in situ, then many possibilities would open up for the conversion of this compound directly into other indole derivatives. It is also apparent that it should be possible to carry out the reaction with substituted thioureas. We shall be exploring these possibilities. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Scheme 1.39. Synthesis of an indole derivative by a three fold cationic polycyclization.

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of W-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2 1 sodium bisulfite-sodium sulfite mixture <00JHC1293>. 

Jones and co-workers reported the ruthenium-catalyzed synthesis of indol derivatives in a single step starting from di-o,o -substituted aromatic isonitriles a representative example is shown in Scheme 77 366>366a... 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

Bosch s group cross-coupled both 2- and 3-indolylzinc derivatives with diversely substituted 2-halopyridines to assemble 2- and 3-(2-pyridyl)indoles, which have become important intermediates in indole alkaloid synthesis [23-28]. Thus, l-(phenylsulfonyl)indole (30) was converted to 2-indolylzinc reagent 32, which was then coupled with 2-halopyridine 33 to secure 2-(2-pyridyl)indole 34. 

Scheme 3. Synthesis of 3,4-functionalized indole derivatives 10 and 11 by Alder-ene reactions, i) X=Y, THF, 67 °C [X=Y H20=N+Me2L,...

Intramolecular cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers, and thioethers—Synthesis of phenanthridine, dibenzopyran, and dibenzothiopyran derivatives Having demonstrated the efficiency of this methodology for the preparation of indole derivatives, we prepared the 2-fluoro-phenyl ether and thioether 22 a, b to study their potential as substrates that could afford oxygen and sulfur heterocycles. However, treatment of 22 a, b with fBuLi afforded, after... 

The corresponding reaction of diethyl 1,2-propadienyl phosphonates (sulfones or sulfoxides) with N-phenylhydroxylamine afforded a-anionic N-phenylvinyloxyamine 159, which upon [3,3]-sigmatropic rearrangement led to anionic 2-(2 -oxoalkyl)phe-nylamine 160. Further cyclization provides an efficient synthesis of indole derivatives 161 [84]. 

This strategy was applied to the total synthesis of ( )-cis- and ( )-trans-trikentrin A [159]. Treatment of 194 with acetic anhydride at 160 °C provided indole derivatives via an N-acylation-[4 + 2]-cycloaddition cascade. Deacylation afforded trikentrin A. 

The mechanism of this elegant, surprising, and widely applicable synthesis of indole derivatives was only explained recently (R. Robinson). It must be assumed that the keto-phenylhydrazones, in tautomeric hydrazo-form, undergo a species of benzidine rearrangement which, like the latter, can often occur even in dilute acid solution, e.g. with the phenylhydrazone of pyruvic acid. 

General Procedure for the Hydroformylation/Enamine Formation. Synthesis of Indole Derivatives. A 300 ml autoclave equipped with a magnetic stirrer was charged with the... 

Scheme 12 Synthesis of indole derivatives from styrene-type anilines...

Table 4 Pharmacologically relevant indole derivatives via hydroformylation/Fischer indole synthesis... 

---