Applications of aminocarbazoles in heterocyclic synthesis

Aminocarbazoles are versatile building blocks in organic synthesis. This review focuses on the application of aminocarbazoles to generate a large variety of fused carbazole heterocycles such as pyridocarbazoles, isomeric pyridocarbazoles,

Synthesis of fused Naphthyridines

Introduction
9] In particular, aminocarbazoles and its derivatives have gained much attraction due to their prominent pharmacological activities.  The ino carbazole derivative has the potential of being active against Alzheimer's disease since the presence of an amino group at the indole nucleus has shown promising results as a rehabilitative medicine.31 1-Aminocarbazoles have been identified as Bcl-2 protein inhibitors, 32 NPY5 antagonists, 33 and anion receptors.34 Aminocarbazoles are also useful intermediates for syntheses of various dyes and pigments, stabilizers for polymers, pesticides, photographic materials and diagnostic reagents in cytochemical studies.For example, 3-amino-9-ethylcarbazole has been widely used as a peroxidase suitable for the colorimetric detection of antibodies for the diagnosis of certain diseases.[35][36][37][38] Both polymeric and molecular amorphous derivatives of 3-aminocarbazoles have attracted interest of the researchers due to their semiconductive properties.[39][40][41][42][43] For these considerations, many synthetic approaches have been developed towards the syntheses of aminocarbazoles and their derivatives.][61][62][63][64][65][66][67][68] Aminocarbazoles have been an important synthon to construct pyridocarbazoles, 69 which are well known for their antitumor properties.70,71 Also, aminocarbazoles have been used to prepare pyrimido [5,4-b]carbazole derivatives. 72The main objective of the present survey is to provide the applications of aminocarbazoles in the synthesis of various heterocycles and provide useful and up-to-date data for organic and medicinal chemists.

Synthesis of Pyridocarbazoles
Pyridocarbazoles are important constituents of heteroannulated carbazoles and exhibit a wide spectrum of biological and medicinal activity such as treatment of breast cancer, intercalation into the DNA double helix, inhibition of topoisomerase II, and anti-HIV agent.

Scheme 4
Propargylation of N-tosylated aminocarbazole 13 with propargyl bromide in the presence of K 2 CO 3 in THF offered propargylated aminocarbazole 14 with good yield.The obtained product 14 was subjected to Sonogashira coupling with various aryl iodides in the presence of Pd(PPh 3 ) 2 Cl 2 and CuI in THF yielded disubstituted alkynes 15.Then iodocyclization reaction with iodine and NaHCO 3 in acetonitrile produced the corresponding iodo-substituted dihydropyridocarbazole derivatives 16 in good yields (Scheme 4).

Synthesis of Isomeric Ellipticine Derivatives
Ellipticine, an alkaloid and several of its derivatives exhibit promising results in the treatment of osteolytic breast cancer metastases, brain tumors, kidney sarcoma, and myeloblastic leukemia. 80ore recent studies have also indicated activity against HIV. 81The main reason for the interest in ellipticine and its derivatives for clinical purposes is their high efficiency against several types of cancer, limited toxic side effects, and a complete lack of hematological toxicity. 82n efficient, three component, one-pot synthesis of new isomeric ellipticine derivatives 19, 20 were prepared through an intermolecular imino Diels-Alder reaction of 3-aminocarbazoles 1 and benzaldehyde 17 with electron-rich alkenes 18 such as 3,4-dihydro-2H-pyran, 2,3-dihydrofuran and ethyl vinyl ether catalyzed by InCl 3 (10 mol%) in ionic liquid (Scheme 5). 83In the case of substituted benzaldehydes, reductive amination was observed.

Scheme 5
Similarly, a mild, efficient and highly selective approach to the synthesis of cryptolcarbazole derivatives 22 via three-component reactions of 3-amino-9-ethylcarbazole 1 and aromatic aldehydes 21 with electron-rich alkenes 18 was reported (Scheme 6). 84It was found that the tetrahydropyran ring and six-membered piperidine rings were cis fused and trans to Ar substituent.Products were obtained in good to high yields, with high selectivity being confirmed by X-ray diffraction analysis.

Scheme 6
Various isomeric ellipticine derivatives were synthesized from aminocarbazoles utilizing a novel [4+2] cycloaddition reaction (Scheme 7). 85The imino Diels-Alder reaction of Nprenylated-2-formyl-3-chloroindole 23 with various substituted aminocarbazoles 1 in the presence of La(OTf) 3 (10 mol %) under the optimized conditions yielded the corresponding imino Diels-Alder products 24 in excellent yields.Cycloaddition of 1 with 25 at 100 °C proceeded efficiently in 1,4-dioxane to afford 26 in excellent yield with higher diastereoselectivity ratio; the cis isomer is the major product.Similarly, the reaction of aminocarbazoles 1 with aliphatic aldehyde 27 as a dienophile proceeded smoothly to afford 28 with good yield.Interestingly, in this case the trans isomer was the major product.

Scheme 7
In another work, a one-pot synthesis of isomeric ellipticine derivatives through CuI/La(OTf) 3 catalyzed sequential inter/intramolecular cyclization of substituted alkynes with imines followed by aromatization was reported (Scheme 8). 86The reaction of imine derived from aminocarbazole 1 and aldehyde 29 with phenylacetylene 30 in the presence of CuI/La(OTf) 3 in [Bmim]BF 4 afforded 31 along with the side product.One equivalent of imine underwent the cyclization with phenylacetylene to dihydropyridocarbazole, which further aromatized to the product 31.CuI was found to be efficient and necessary catalyst to activate the triple bond.It was observed that substituents having an electron poor or electron rich or heteroaromatic group gave the desired products in good to excellent yields.The reaction of O-propargylated salicylaldehydes 32 with 3-aminocarbazole 1 in the presence of CuI/La(OTf) 3 in ionic liquid yielded the corresponding intramolecular cyclization products 33 in excellent yields and the cyclization occurs through the fourth position of the carbazole ring (Scheme 9).

Scheme 9
Similarly, the intermolecular reaction of diaminocarbazole 1 with benzaldehyde 17, phenylacetylene 30 under the same reaction conditions proceeded well and furnished the corresponding product 34 in 62% yield (Scheme 10).The structure of the product 34 was confirmed by single crystal analysis.Also, the intramolecular pathway of diaminocarbazole 1 with O-propargylated salicylaldehyde 32 gave the product 35 in 76% and there was no monocyclized product observed.
A one-pot synthesis of quinolines via molecular iodine-catalyzed and air-mediated tandem condensation/imino-Diels-Alder/isomerization/oxidation of simple readily available amines, aldehydes, and alkynes was reported. 87This methodology was extended to the polycyclic aromatic 9-ethylcarbazol-3-amine.The reaction of 9-ethylcarbazol-3-amine 1, benzaldehyde 17 and phenylacetylene 30 in nitromethane in the presence of molecular iodine and air produced the ellipticine isomer 36 in 68% yield (Scheme 11).This has been done by assembling the quinoline core via a one-pot three component reaction from [3+2+1] atom fragments by formation of three new bonds.

Scheme 12
Following a similar strategy, demethylated analogues of ellipticine were prepared from various 3-aminocarbazoles 1 via the corresponding imino-1,2,3-dithiazoles 40.Whatever thermolysis conditions were used, the wanted linear thiazolocarbazolecarbonitriles 42 were the minor products, whilst their angular counterparts 41 were the major ones (Scheme 13).

Synthesis of Pyrimidocarbazoles
The ethoxycarbonyl protected guanidine intermediate 46 was prepared in two steps realized in one-pot and in nearly quantitative yield from 3-aminocarbazole 1.The intermediate 46 was subjected to Friedel-Crafts intramolecular cyclization under microwave irradiation using montmorillonite K-10 clay as a catalyst to gave tetracyclic pyrimido [4,5-c]carbazole 47 in 77% yield (Scheme 15). 91The pyrimido[4,5-c]carbazole derivative showed significant micromolar IC 50 against cancer cell lines.

Synthesis of Pyrrolo-and Indolo-carbazoles
Pyrrolo[2,3-a] and [3,4-c]carbazoles have great importance due to their inhibiting properties toward pim kinase inhibitors 93 and Chk1 inhibitors, 94 respectively.Indolocarbazole, the benzene analog of pyrrolocarbazole have received great attention because of their existence in many natural products with potent biological activities. 95yrrolo[2,3-c]carbazoles 52 were synthesized from N-alkylated-3-aminocarbazoles 1 and ethylene glycol 51 via heteroannulation reaction using RuCl 3 /SnCl 2 (Scheme 17). 96The best yields were obtained when the reactions were carried out in toluene.It was observed that without the addition of SnCl 2 heteroannulation reaction did not proceed.RuCl 3 was found to be an efficient catalyst in this reaction compared with other catalysts.The authors found that dppe was the most effective ligand for this reaction.The desired indolo[2,3-c]carbazoles 54 were successfully synthesized in good yields by reacting acetonylacetone 53 with various pyrrolo-[2,3-c]carbazoles 52 using p-toluenesulfonic acid as a catalyst.

Synthesis of Quino-and Chromeno-carbazoles
Quino and chromenocarbazoles were synthesized from aminocarbazoles in two steps based on C-N and C-O bond formation through Ullmann-Goldberg condensation followed by intramolecular Friedel-Crafts cyclization. 98As shown in Scheme 19, the condensation of 3amino-9-ethylcarbazole 1 with various o-iodobenzoic acids 57 in presence of CuI and K 2 CO 3 without any ligand in DMSO at 80 ºC to give products 58.The later compounds 58 were subjected to cyclization with POCl 3 at 60 ºC to afford the corresponding products 59 in good yields.The reaction works well for other substituted o-halobenzoic acids.When the reaction was performed at 120 ºC, two regioisomeric quinocarbazoles were formed.Compounds 60 were formed as a major products along with minor products 61 (Scheme 19).

Synthesis of other Heterocycles
A three-component synthesis of exo-tetrahydroindolo [3,2-c]quinoline derivatives 65 from the reaction of an aromatic aldehydes 21, 9-ethyl-9H-carbazol-3-amine 1 and indoles 64 with iodine as catalyst in toluene was reported (Scheme 21). 101The advantages of this method include mild reaction conditions, moderate yields, high stereoselectivity, metal-free catalyst, and operational simplicity.

Scheme 21
Diindolophenazine derivatives 66 were synthesized by the aerobic oxidative coupling of 3aminocarbazoles 1 in the presence of catalytic CuBr in DMSO at 80 ºC while open to air (Scheme 22). 102After screening a variety of solvents and catalysts, the best result was obtained in DMSO at 80 ºC for six hours using copper(I) bromide as the catalyst.DMSO may play the role of ligand by coordinating the copper salts.A variety of substituents such as Me, OMe, Cl, Br are tolerated well on the aminocarbazole.

Scheme 23
The reaction of aromatic aldehydes 21, 3-amino-9-ethylcarbazole 1 and mercaptoacetic acid 67 under microwave irradiation (MW) under solvent free conditions offered the corresponding 1,4-thiazepine derivatives 69 (Scheme 24). 104The screen of solvent revealed that solvent-free condition was the best suitable condition for this reaction.These compounds have been subjected to testing for in vitro antioxidant and cytotoxic activities, resulting in the finding that these 1,4thiazepine derivatives not only have significant antioxidant activity, but also exhibit remarkably selective cytotoxicity to carcinoma cell line HCT 116.
Microwave-assisted eco-friendly four component reaction of 3-amino-9-ethylcarbazole 1, aromatic aldehydes 21, malononitrile 70 and acetylenic esters 71 using indium trichloride as catalyst offered N-carbazolyldihydropyridines 72 in good yields (Scheme 25). 105The transformation was believed to proceed via Knoevenagel condensation, Michael addition, followed by tautomerization leading to the formation of products.The remarkable catalytic activity of InCl 3 ARKAT-USA, Inc was superior to the other reported catalysts.Dimethyl acetylenedicarboxylate also showed very high reactivity.The use of microwave heating reduced reaction times and resulted in higher yields.

Scheme 27
Carbazole-based α-aminophosphonates 107 are known to possess considerable microbial and antioxidant behavior.The Kabachnik-Fields reaction of aminocarbazole 1 with aromatic aldehydes 21 and diphenyl/dialkyl phosphites 77 in the absent of catalyst under neat conditions at 25 o C gave the corresponding α-aminophosphonates 78 (Scheme 28). 108This protocol has advantages of absence of catalyst under mild conditions and short period of times.The structure for one of these compounds has been confirmed by X-ray crystallography.

Scheme 28 10. Conclusions
This review highlights the advances in the use of aminocarbazoles as starting materials in the synthesis of wide variety of heterocycles of carbazole framework.Aminocarbazoles can become promising tools for diversity oriented synthesis.