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Indole alkaloids constitute a large class of natural products and their diverse and complex structures have been attributed to potent biological activities such as anticancer, anti-inflammatory, antimicrobial, antimalarial, antiplasmodial and protein kinase inhibition. The isolation of bioactive compounds from natural sources is difficult, costly and an extremely time-consuming process, therefore synthetic pathways are more convenient than natural separation to deliver such compounds in considerable amounts. In this respect, this review provides comprehensive information on the structures and the synthesis of bioactive indole alkaloids utilizing 1H-indole-3-carboxaldehyde and its derivatives as starting compounds. 1 Overview2 Phytoalexins2.1 Brassinin, Cyclobrassinin and Brassitin2.2 1-Methoxybrassinin, 1-Methoxyspirobrassinol and 1-Methoxyspirobrassinin2.3 4-Methoxybrassinin and 4-Methoxycyclobrassinin2.4 Cyclobrassinone2.5 Brassilexin2.6 (S)-(–)-Spirobrassinin2.7 Camalexin3 Bis(indole) Alkaloids: Rhopaladines A–D4 Coscinamides A and B5 α-Cyclopiazonic Acid6 Dipodazine7 Isocryptolepine8 Apparicine9 Carbazole Alkaloids: Mukonine and Clausine E10 Indolmycin11 Conclusion

Formylated chlorothieno[2,3-b]pyridine derivatives were synthesized by reaction between N-protected 3-acetyl-2-aminothiophenes and Vilsmeier–Haack reagent under classical conditions. These products were not accessible without N-protection of the starting materials or by reaction between the reagent and 4-chlorothieno[2,3-b]pyridine under any conditions. The conditions of the reaction could be altered to produce unformylated derivatives in better yields than reaction with unprotected aminothiophene.

A two-step synthesis of polyfunctionalized aminothieno[3,2- b ]furans and aminothieno[3,4- b ]furans is described and discussed. It was found that O-alkylated thiophenes bearing electron-withdrawing groups in the ortho -position undergo condensation in the presence of an excess of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Furthermore, selective condensation on an ortho -nitrile substituent in preference to ortho -ester or ortho -ketone substituents was observed.

A series of novel thieno- and benzothieno[3,2- D]pyrimidin-4(3 H)-onesis synthesised via condensation of 3-amino(benzo)thiophene-2-carboxylateswith various lactams.

The preparation of new N-substituted 2-arylimino-1,3-thiazolidin-4-ones from 5-substituted-3-aminothiophenes using an easy three-step procedure is described.

New 4-amino-2-arylthieno[2,3-d]pyrimidines were synthesized by reacting 2-amino-3-cyanothiophenes and aryl nitriles under microwave irradiation. Functionalization of 4-amino group was made by acetic anhydride and several isocyanates.

5-Substituted 3-amino-selenophene-2-carbonitriles and 2-substituted 4-amino-1,3-selenazole-5-carbonitriles were reacted with sodium nitrite in hydrochloric acid to give chloroselenolotriazines and chloroselenazolotriazines. These compounds were then subjected to S N Ar reactions with secondary amines under microwave irradiation.

Substituted 3-acetoxy-1-acetyl-1H-indoles were pre- pared by condensing 2-chlorobenzoic acids with amino acids under Ullmann conditions in good yields, and further cyclodecarboxyla- tion using the Rossing method in moderate to good yields. N,O-Diacetylindoxyls (1-acetyl-1H-indol-3-yl acetates, 3-acetoxy-1-acetyl-1H-indoles) are present as precursors of some aglicons in chromogenic compounds that are very useful in the identification of various microorganisms. 1-3 However, 2-substituted 3-acetoxy-1-acetyl-1H-indoles are rarely found in literature and there are no procedures available that describe the synthesis of these compounds from the corresponding unactivated amino acid and 2- chlorobenzoic acids by the Ullman procedure. Neverthe- less, 2-substituted 3-acetoxy-1-acetyl-1H-indoles have been used as the starting point for the preparation of 2- substituted 1-acetyl-1,2-dihydro-3H-indol-3-ones. 4 On the other hand, only one compound, 3-acetoxy-1- acetyl-2-methyl-1H-indole, has been prepared from the corresponding N-acetylated 2-((carboxymethyl)ami- no)benzoic acid, but it was not prepared using the Ullman conditions. 4 In previous work we reported a simple two-step procedure for the preparation of 3-acetoxy-1-acetyl-6-chloro-1H-in- dole from 2,4-dichlorobenzoic acid and an unactivated amino acid in good yield. 5 Encouraged by this result, we decided to carry out the preparation of other substituted 3- acetoxy-1-acetyl-1H-indoles starting from the corre- sponding 2-chlorobenzoic acids. 6 These papers made us think about the possibility of using the same procedure to prepare 2-substituted 3-acetoxy-1-acetyl-1H-indoles 6 from 2-chlorobenzoic acids 1 and 2-substituted amino acids 2 or 5-aminopentanoic acid (3). We started by using the same reaction conditions given in previous papers and using 2-chlorobenzoic acids 1a-d and amino acids 2a-c or 3 to give Ullman compounds, 2-((carboxymethyl)ami- no)benzoic acids 4a-g and 5a-c (Table 1) in very good yields. Subsequent Rossing cyclodecarboxylation of 4a-g allowed us to obtain 2-substituted 3-acetoxy-1-acetyl-1H- indoles 6a-g in moderate to good yields (Table 2).

Microwave-assisted synthesis allowed efficient access to 4-chloroselenolo[3,2-d]pyrimidines in short times and very good a yields. Some functionalizations by S N Ar and palladium-catalyzed reactions are also reported.

New 3-amino-2-selenophenecarbonitriles condensed with cyclanones to afford, in one step, analogues of Tacrine. A comparison between classical heating and microwave irradiation for the Friedlander condensation is presented.

Substituted 7-hydroxythieno[3,2- B]pyridin-5(4 H)-ones were prepared from the corresponding β-chloropropenonitriles in one step.

β-Chloroacroleins reacted readily with lactams and several heteroarylamines (aminopyridines, aminoquinoline and azoles) under standard Buchwald-Hartwig amination conditions. Both Pd(OAc) 2 /Binap or Pd(OAc) 2 /Xantphos were efficient catalytic systems in the presence of Cs 2 CO 3 as base.

N-Acylated photoactivatable analogues of glutathione bearing an aryl azide moiety were synthesized for the first time starting from S-tritylglutathione.

The N-arylation of hetarylamines by reaction of aminopyridines or aminoquinolines with substituted bromothiophene-2- or -3-carboxylates is described. From 2-aminopyridines and 1-aminoisoquinoline, polycyclic compounds were obtained in one-pot, two-step reactions: C-N coupling is followed by intramolecular cyclization involving the nitrogen atom of the heterocyclic ring and the carboxylate. Steric hindrance seems to be a limitation for the latter reaction, because when 2-amino-6-picoline was used, the corresponding dihetarylamines were obtained.

New photoactivatable analogues of glutathione disulfide (GSSG) bearing new benzophenone-like photophores were synthesized by using an improved coupling reaction.

We describe here the palladium-catalyzed amination of polysubstituted bromothiophenes under mild conditions (using Cs 2 CO 3 as base). Anilines bearing electron-donating groups gave good results whereas anilines with electron-withdrawing substituents required greater catalyst loadings and gave lower yields.

1-Aryl-2-thienyl-substituted pyrroles and/or 5-arylamino-2,2´-bithiophenes were synthesized by treatment of arylaminothieno-oxobutanamides with Lawesson’s reagent. These in turn were prepared by direct amidation of 4-oxo-(2-thienyl)butanoic acid through DCC–BtOH mediated reactions., Fundação para a Ciência e Tecnologia (FCT)

The preparation of terpyridine ligands under solventless conditions is presented. A new procedure using alumina as the base is described. This new procedure was applied to the preparation of new terpyridines.

Substituted selenolo[2,3-b]thiophenes 4 and selenophenes 5 can be easily synthesized in two steps from ketene dithioacetals 1.

A two steps simple synthesis of 2,3,4,5-functionalised thieno[2,3-b]thiophenes 2-6 from ketene dimethylthioacetals is described.

New substituted 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-diones were synthesized in seven steps, starting from substituted u-methylene ketones, via 3-aminothiophene-2-carboxylic acid alkyl esters.

2-Aminothieno[3,2-d]pyrimidin-4-ones were synthesized in one step by condensation of 3-amino(benzo)thiophene carboxylate with chloroformamidine hydrochloride.

Coumarin derivatives were prepared using zirconyl chloride octahydrate (1%) as a Pechmann catalyst, either neat or in some cases employing small volumes of ethanol as solvent. As result of this work, coumarins were obtained in moderate to good yields.