1,1,2-Trimethyl-1H-benz[e]indole: Key Heterocyclic Intermediate

1,1,2-Trimethyl-1H-benz[e]indole, also known as the photoinitiator TMBI, 2,3,3-trimethyl-4,5-benzo[e]indole, etc., is an important basic heterocyclic compound. It is typically synthesised from naphthylamine derivatives through steps such as cyclisation and methylation. As a key intermediate, its primary application lies in the synthesis of benzoindocyanine dyes and photochromic dyes, finding widespread use in the fields of indigoid dyes and electroluminescent materials. Furthermore, 1,1,2-Trimethyl-1H-benz[e]indole can serve as a pH fluorescent probe for intracellular pH detection and labelling, and can also be used to prepare biomedical tools such as near-infrared optical probes for tumour imaging and hypoxia-sensitive probes for real-time ischaemia imaging. Cyanine dyes containing this structure can also be utilised as non-linear optical materials, infrared laser dyes and CTP infrared absorbers, holding significant value in pharmaceutical synthesis and materials science.

1,1,2-Trimethyl-1H-benz[e]indole in chemical synthesis

2- Naphthylhydrazine hydrochloride (0.2500g, 1.29mmol), 3-methyl-2-butanone (0.1107g, 1.29mmol) were refluxed at 115°C for 2 hours under acetic acid (4ml) and nitrogen protection, and removed after the reaction was over The solvent was passed through a silica gel column with a developing solvent of petroleum ether and ethyl acetate (volume ratio 4:1) to obtain the intermediate 1,1,2-Trimethyl-1H-benz[e]indole (0.2318 g, 1.11 g mmol, yield 86.05%). 1,1,2-Trimethyl-1H-benz[e]indole (0.2318 g, 1.11 mmol), 6-bromohexanoic acid (1.0293 g, 5.3 mmol) were combined in acetonitrile (4 ml) under nitrogen Reflux at 105°C for 30 hours, remove the solvent, dissolve with 1.5ml of dichloromethane, then add 1.5ml of diethyl ether to separate out the solid, filter and collect the solid to obtain the product 3-(5-carboxypentyl)- 1,1,2-Trimethyl-1H-benz[e]indole -3-onium (0.3305 g, 1.02 mmol, 91.89% yield). 3-(5-Carboxypentyl)-1,1,2-trimethyl-1H-benzo[e]indole-3-onium (0.3305 g, 1.02 mmol), N-[(1E,3E) -3-(Phenylimino)prop-1-en-1-yl]aniline (0.2493, 1.12 mmol) was dissolved in a mixed solution of 4 mL of acetic acid and 4 mL of acetic anhydride, and refluxed at 115°C for 3.5 hours under nitrogen. After the reaction was completed Removal of solvent gave crude solid 3-(5-carboxypentyl)-1,1-dimethyl-2-((1E,3E)-4-(N-phenylacetamide)butane-1,3- Dien-1-yl)-1H-benzo[e]indole-3- onium (0.5053 g, 1.02 mmol, 99.99% yield).[1]

Annulation reaction of 1,1,2-Trimethyl-1H-benz[e]indole with acrylic acid

During the last decade, there has been a significant increase in the use of 1,1,2-Trimethyl-1H-benz[e]indole as a precursor for the synthesis of fluorescent organic molecules that have wide biomedical and technical applications. In particular, this starting material was successfully used for the preparation of a number of near-infrared fluorescence emitting dyes. These dyes were used as labelling agents for biomolecules and probes for high-contrast fluorescence imaging of biological tissues, as well as novel fluorophores for multiple-mode molecular logic systems or enzyme sensing in biological assays. Furthermore, blue organic squaraine dyes containing the 1,1,2-Trimethyl-1H-benz[e]indole nucleus were used for dye-sensitized solar cell applications. The corresponding 2-methylidene bases, derived from 1-alkyl-2,3,3-trimethyl-3H-indolium salts, act as C-nucleophiles when reacted with acrylamide to yield spiro[indole-2,2′-piperidine] derivatives. Recently, the similar coupling of 2-methylidene-1H-benzo[e]indole with acrylamide was utilized for the preparation of novel fluorescent scaffolds. Finally, the condensation of 2,3,3-trimethyl-3H-indoles with 2,3-unsaturated aldehydes and ketones provides pyrido[1,2-a]indolium salts that have been applied to the synthesis of optical brighteners and dyes for synthetic fibres, while their formylation afforded the corresponding dialdehydes, as synthons for the preparation of 2-(pyrazol-4-yl)-3H-indole derivatives. The aim of the present work is the synthesis of fluorescent building blocks through the reaction of 1,1,2-Trimethyl-1H-benz[e]indole with acrylic acid and further chemical transformations of the obtained adducts.[2]

The reaction of 1,1,2-Trimethyl-1H-benz[e]indole with acrylic acid and its derivatives was employed for the preparation of novel fluorescent building blocks. Treatment of 1,1,2-Trimethyl-1H-benz[e]indole with acrylic acid, acrylamide or tert-butyl acrylate in an autoclave or a microwave reactor at 180–200 °C afforded benzo[e]pyrido[1,2-a]indole derivatives. Various chemical transformations of the latter compounds have been performed to yield functionalized benzo[e]indole scaffolds. The structure assignments were based on data from 1H and 13C NMR spectroscopy and single crystal X-ray analyses. The optical properties of the obtained benzo[e]indoline derivatives were studied by UV–vis and fluorescence spectroscopy.

References

[1]CN114853743A

[2]Steponavičiūtė, R., Martynaitis, V., Bieliauskas, A., & Šačkus, A. (2014). Synthesis of new fluorescent building blocks via the microwave-assisted annulation reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives. Tetrahedron, 70(11), 1967–1974.

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