Regioselective bromination of substituted 2'-hydroxy chalcones and synthesis of fused nitrogen heterocycles

My sincere regards to all the faculty members of the Department of Chemistry, IIT Guwahati, for their motivation and encouragement. The content of the thesis entitled "Regioselective bromination of substituted 2'-hydroxy-chalcones and synthesis of fused nitrogen heterocycles" is divided into two main parts, namely Part A and Part B.

GENERAL REMARKS

PART A

Brief Review on Hydroxy and Bromochalcones

Introduction

Prehistoric therapeutic uses of chalcones can be linked to the thousand-year-old use of plants and herbs for the treatment of The concept of “microwave-induced organic reaction enhancement”26 chemistry has proven very useful in the efficient synthesis of chalcones.

Figure 2. The general structure of chalcones

Halogenated Chalcones

They also found that antiproliferative activity of halogenated derivatives increases when the substituent in the 3- or 4-position of the B ring goes from F to Cl and to Br. Ramirez-Tagle and group synthesized 88 2'-hydroxychalcones with different methoxy substitutions on ring B (Figure 16) and evaluated the relationship between the structural characteristics of the synthetic chalcones and their antitumor activity.

Aureusidin biosynthesis

As the chalcones contain a double bond in the vicinity of a ketone group, the action of bromine on them affords an interesting study. Phloroglucinol-based chalcones are an important synthetic precursor for natural flavonoids such as Vitexin, 105 Aciculatin.106 Since Kostanecki and Tambor107 reported nuclear substitution in the bromination of phloroglucinol-derived chalcones, other workers108-110 have assumed that to form a tribromide .

Results and Discussion

Retrosynthetic Analysis of Vitexin

Synthesis of the compound 8-bromo-5,7,4'-trimethoxyflavone was first reported by Wheeler and Hutchins121 from the corresponding 2'-hydroxy-4,4',6'-trimethoxychalcone by bromination using molecular bromine followed by cyclization under basic conditions. Accordingly, the extent and generality of the response was also investigated with increased amounts of BDMS.

Table 1 Optimization of the reaction conditions a

Synthesis of 8-bromoflavones

It is a well-known fact that (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-aryl-2-propen-1-ones are key starting materials for the synthesis of flavones and aurones. Then, compound 4a was further transformed to 7-bromoauron (6a) by treatment with 0.2 M ethanolic KOH solution (Scheme 12).

Synthesis of 7-bromoaurones

The reaction mixture was extracted with DCM (2x15 mL), washed with water and dried over anhydrous sodium sulfate. The reaction mixture was extracted with DCM (2×15 mL), washed with water and dried over anhydrous sodium sulfate.

Part A (Chapter 1 & 2)

PART B

Brief Review on Exploration of Tandem Knoevenagel-Michael Reaction through Multi-component Reactions (MCRs) in

Organic Synthesis

Prebiotic synthesis of adenine

The first modern contribution to the development of multicomponent chemistry by Strecker5 was the synthesis of α-aminonitrile derivatives involving condensation of an aldehyde or a ketone with amine and hydrogen cyanide. Sequential reactions, where the functionality for the second reaction is created, but additional reagents must be added to achieve the second reaction. A simple and convenient method for the one-pot three-component synthesis of 3-pyranyl indoles was accomplished by tandem Knoevenagel-Michael reaction of 3-cyanoacetyl indole, various aromatic aldehydes and malononitriles catalyzed by InCl3 in ethanol in good yields under reflux conditions (Scheme 17).17.

Later, the same group used this cascade Knoevenagel condensation/Michael addition/cyclization sequence for the synthesis of highly functionalized 4H-thiopyrans (Scheme 18).18. The synthesis of functionalized tetrahydropyranones has been achieved at room temperature with iodotrimethylsilane by a tandem Knoevenagel condensation of aldehydes with aldol adducts, prepared from β-ketoesters and aldehydes, followed by a Michael reaction giving the THP products (Scheme 19).19 . Tricyclic thiochromeno[2,3-b]pyridine derivatives have been successfully synthesized from ortho-halo-β-aroylthioamides, Meldrum's acid and aromatic aldehydes in an unusual one-pot multicomponent tandem reaction (Scheme 22).22 The reaction presumably proceeds via Knoevenagel condensation- Michael addition-cyclocondensation-decarboxylation-rearrangement reaction sequence to form the final product.

The procedure involves the initial reaction of dimedone and an aldehyde to form the Knoevenagel product, which reacts with phthalhydrazide via a Michael reaction to form the final product indazolo[2,1-b]phthalazine-trione (Scheme 25).25. In conclusion, the above discussion clearly demonstrates the diversity and power of the tandem Knoevenagel-Michael reaction in the field of synthetic organic chemistry.

Synthesis of 2 H -indazolo[2,1- b ]phthalazine-triones by Using an Efficient and Reusable Catalyst Ferric sulfate

Synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives

In order to find suitable reaction conditions, benzaldehyde (1.2 mmol), dimedone (1 mmol) and phthalhydrazide (1 mmol) were chosen as model substrates. The reactions were studied in the presence of different catalysts in different solvent systems and the results are summarized in Table 4. Interestingly, the desired product 10a was isolated in 40% yield (Table 4, entry 4) when the same reaction mixture was heated in the presence 5 mol% of hydrated ferrous sulfate.

From these observations, we concluded that 20 mol% catalyst is a suitable choice for the best yield. However, we used hydrated ferrous sulfate because it gives high yields and can be reused. Similarly, cyclohexane-1,3-dione also provided the desired 2H-indazolo[2,1-b]phthalazine-trione derivatives (10p-u) in high yields under the same reaction conditions.

In view of greener chemistry, efficient catalyst recovery and reuse are highly desirable. In fact, the Fe2(SO4)3xH2O catalyst was easily recovered from the reaction mixture at the end of the reactions and reused four more times for the same set of reactions.

Table 4. Optimization for one-pot condensation of phthalhydrazide, benzaldehyde and dimedone a

Synthesis of 2 H-indazolo[2,1-b]phthalazine-trione using an efficient and reusable ferric sulfate catalyst Efficient and reusable ferric sulfate catalyst. After completion of the reaction (as monitored by TLC), it was brought to room temperature. The solid product 10 precipitated after adding 6 mL of water to it and was filtered through a Büchner funnel.

After completion of the reaction, the catalyst was recovered by removing ethanol in a rotary evaporator, followed by addition of 15 mL of CH2Cl2. The catalyst precipitated due to its poor solubility in CH2 Cl2 and was filtered off through a Büchner funnel. The reusability of the recovered catalyst was examined five times in succession using the same substrates.

Synthesis of Chromeno[3,4- b ]quinolin-6,11-dione Derivatives via One-pot Three Component Reactions Using TBATB

A few years ago, Chaudhuri and his collaborators first reported the environmentally friendly synthesis of TBATB and its use in bromination reactions.56 Later, our group also demonstrated its utility for the deprotection of dithioacetals,57 an inter-conversion of carbonyl compounds to 1, 3-oxathiolanes and conversely,57b synthesis of α-bromenones,57c piperidines57d and naturally occurring flavone derivatives57e as well as in carbohydrate chemistry.57f A wide variety of organic transformations have also been developed by other groups using TBATB.58 Knowing the unique behavior, properties and stability of organic ammonium tribromides , we conceived that TBATB could act as a useful catalyst for the one-pot synthesis of Chromeno[3,4-b]quinoline-6,11-dione derivatives (12) from aromatic aldehydes (8), cyclic 1,3 -diketones (9) and 3-aminocoumarins (11) (Scheme 29). To find out the optimized reaction conditions for the synthesis of Chromeno[3,4-b]quinoline-6,11-diones, one-pot three-component reaction was carried out using dimedone (1.0 mmol), benzaldehyde (1.0 mmol) and 3-aminocoumarin (1.0 mmol) in ethanol under reflux conditions in the presence of 5 mol% TBATB, and the desired product 12a was isolated in 54% yield. It was noticed that the yield of the product did not increase significantly by increasing the amount of catalyst from 10% to 20%.

From these observations it appeared that 10 mol% of the catalyst is sufficient to obtain the best result. To investigate the efficiency of the catalyst, similar reactions were carried out in the presence of other catalysts such as FeCl3.6H2O, HCl, aq 48% HBr and HClO4-SiO2 (Table 7, entries 7-10). In summary, we have provided an effective route for the synthesis of a series of Chromeno[3,4-b]quinoline-6,11-dione derivatives via one-pot three-component reaction.

Synthesis of Chromeno[3,4-b]quinolin-6,11-dione derivatives via one-pot three-component reactions using TBATB. One-pot three-component reactions using TBATB. Synthesis of benzo[f]chromeno[3,4-b]quinolin-6-one derivatives using TBATB catalyst via one-pot three-component reaction.

Table 8. Substrate scope of chromeno[3,4-b]quinoline-6,11-dione derivativesEntry Catalyst Solvent Catalyst

Synthesis of Benzo[ f ]chromeno[3,4- b ]quinolin-6-one Derivatives Using TBATB Catalyst via One-pot Three Component Reaction

In this chapter, we report the one-pot synthesis of benzo[f]chromeno[3,4-b]quinolin-6-one derivatives (14) involving aromatic aldehydes (8), 2-naphthol (13) and 3- aminocoumarin (11) in n-butanol using 10 mol% of TBATB catalyst under reflux conditions trapping a 2-naphthoquinone-1-methide intermediate (Scheme 31). Increasing the amount of TBATB from 10 to 20 mol% did not improve the yield of product 14b. It was observed that when the reaction was carried out in n-butanol in the presence of 10 mol% TBATB, the yield of product 14b increased significantly (Table 10, entry 5).

The reaction of some other aromatic aldehydes was studied with 2-naphthol and 3-aminocoumarin under identical reaction conditions, resulting in products 14c–g (Table 11, entries 3–7) in good yields. We believe that TBATB reacts with n-butanol to generate dry HBr in the reaction medium, which actually catalyzes product formation. In summary, we have provided an efficient route for the synthesis of a series of benzo[f]chromeno[3,4-b]quinolin-6-one derivatives via one-pot three-component reaction.

Synthesis of benzo[f]chromeno[3,4-b]quinolin-6-one derivatives using TBATB catalyst via one-pot three-component reaction. After completion of the reaction, the reaction mixture was brought to room temperature and n-butanol was removed in a rotary evaporator.

Table 10. Optimization of reaction conditions for synthesis of benzo[f]chromeno[3,4- benzo[f]chromeno[3,4-b]quinolin-6-one (14b) a

Part B (Chapter 1, 2, 3 and 4)

Phytochemical Dictionary – A Handbook of Bioactive Compounds from Plants, 2e eds., Taylor & Francis, Londen: VK, 1999.

APPENDIX

Conclusion and Future Perspectives

Moreover, the synthesis of optically active chromeno[3,4-b]quinoline-6,11-dione derivatives and benzo[f]chromeno[3,4-b]quinoline-6-one derivatives can be further explored using asymmetric organocatalysts. Regioselective monobromination of (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-aryl-propen-1-ones using bromodimethylsulfonium bromide and synthesis of 8- bromoflavones and 7-bromoaurones Abu T. Regioselective monobromination of (E)-1-(20-hydroxy-40,60-dimethoxyphenyl)-3-aryl-2-propen-1-ones using bromodimethylsulfonium bromide and synthesis of 8-bromoflavones and 7-bromouranes.

Therefore, the synthesis of brominated 20-hydroxychalcones is highly desirable from a biological point of view. It is a well-known fact that (E)-1-(20-hydroxy-40,60-dimethoxy-phenyl)-3-aryl-2-propen-1-ones are important starting materials for the synthesis of flavones and aurones. . Hydrated iron sulfate can be used as an efficient and reusable catalyst for the synthesis of 2H-indazolo[2,1-b]phthalazine trione derivatives via a one-pot three-component condensation reaction of phthalhydrazide, aromatic aldehydes, and cyclic-1,3-diketones in ethanol under reflux conditions.

In this article, we reported hydrated ferrous sulfate catalyzed one-pot synthesis of 2H-indazole[2,1-b]phthalazinetrione derivatives via three-component condensation reaction of phthalhydrazide, aromatic aldehydes and cyclic 1,3-dicarbonyl compounds in ethanol under reflux conditions as shown in Scheme 1. After completion of the reaction (as monitored by TLC), it was brought to room temperature.

Figure 1. Some naturally occurring flavonoids.