Regioselective Synthesis of 5-Propyl-2-((trityloxy)methyl) thiophene-3-carbaldehyde

: 5-propyl-2-((trityloxy)methyl)thiophene-3-carbaldehyde was synthesized by using the concept of chemo-and regioselective Br/Li exchange reaction from 3-bromo-5-propyl-2-((trityloxy)methyl) thiophene. This is a ﬁve-step protocol starting from thiophene with an overall yield of 33%. These lithium/halogen exchange reactions were carried out at − 78 ◦ C to rt over the period of 1 to 18 h depending on the reactivity of electrophiles.


Introduction
Alkylated thiophene-3-carbaldehyde is a widely used building block for organic synthesis of a myriad of materials with multiple applications.It has been used as the key starting material for organic field-effect transistors [1][2][3][4][5], glucagon antagonist [6], inhibitors of D-amino acid oxidase [7], dopamine 1 agonist ABT-431 (Figure 1) [8,9], and water-soluble fluorescent polymers [10].Due to their strong luminescence properties, thiophene-based compounds have also been used for dye-sensitized organic solar cells and light emitting devices [11] as well as nonlinear optical chromophores [12].Thiophene-derived small organic molecules have shown to possess many biological applications, such as antitumor [13], analgesic [14], and anti-inflammatory [15] treatments.One example compound of interest is dopamine d1 adonist ABT-431 (Figure 1), which consists of a trialkyl-substituted thiophene that could be readily synthesized with an accessibly derivatized thiophene.5-Alkyl-2-((trityloxy)methyl)thiophene-3-carbaldehyde is a very versatile organic molecule by nature, with functionalizable handles that allow facile derivation.The aldehyde group in position 3 allows for immediate reactivity, while a methyl-alcohol can be exposed via deprotection of the trityl group.This system also benefits from its flexibility at position 5, being capable of most stable alkyl functionalizations.In the present study, we report a concise five-step synthesis protocol for a new thiophene derivative, 5-propyl-2-((trityloxy)methyl)thiophene-3-carbaldehyde 1a, starting from thiophene (Scheme 1).

Materials and Methods
All reactions were conducted using oven-dried glassware under an atmosphere of Argon (Ar).Commercial grade reagents were used without further purification.Commercially available anhydrous solvents were used.Flash chromatography was carried out using silica gel (230-400 mesh).TLC was performed on aluminum-backed plates coated with silica gel 60 with F254 indicator.The 1 H-NMR spectra were recorded with a 200 MHz NMR and the 13 C-NMR spectrum was recorded with a 50 MHz NMR at the Department of Chemistry, Indian Institute of Technology, Kharagpur, India. 1 H-NMR chemical shifts are expressed in parts per million (δ) relative to CDCl3 (δ = 7.26). 13C-NMR chemical shifts are expressed in parts per million (δ) relative to the CDCl3 resonance (δ = 77.0).Melting points (m.p.) of solid compounds are reported without correction.Elemental analysis (CHN) was recorded at Department of Chemistry, Indian Institute of Technology, Kharagpur, India. 1 H and 13 C-NMR spectra can be found in the supplementary materials section.

Synthesis of 2,3,5-Tribromothiophene 2 [16]
Thiophene 1 (134 mmol, 11.25 g) and 200 mL of chloroform were charged into a 500 mL, three-necked flask equipped with a stirrer, a dropping funnel, and an outlet for the hydrogen bromide evolution.Bromine (406 mmol, 64.80 g) was added dropwise to the stirred mixture over a period of 2 h in ice cold conditions.Then, the reaction mixture was warmed to room temperature.After the mixture rested overnight, it was heated at 50 °C for 24 h, washed with a 2N sodium hydroxide solution, refluxed for 7 h with a solution of

Materials and Methods
All reactions were conducted using oven-dried glassware under an atmosphere of Argon (Ar).Commercial grade reagents were used without further purification.Commercially available anhydrous solvents were used.Flash chromatography was carried out using silica gel (230-400 mesh).TLC was performed on aluminum-backed plates coated with silica gel 60 with F254 indicator.The 1 H-NMR spectra were recorded with a 200 MHz NMR and the 13 C-NMR spectrum was recorded with a 50 MHz NMR at the Department of Chemistry, Indian Institute of Technology, Kharagpur, India. 1 H-NMR chemical shifts are expressed in parts per million (δ) relative to CDCl 3 (δ = 7.26). 13C-NMR chemical shifts are expressed in parts per million (δ) relative to the CDCl 3 resonance (δ = 77.0).Melting points (m.p.) of solid compounds are reported without correction.Elemental analysis (CHN) was recorded at Department of Chemistry, Indian Institute of Technology, Kharagpur, India. 1 H and 13 C-NMR spectra can be found in the supplementary materials section.

Synthesis of 2,3,5-Tribromothiophene 2
Thiophene 1 (134 mmol, 11.25 g) and 200 mL of chloroform were charged into a 500 mL, three-necked flask equipped with a stirrer, a dropping funnel, and an outlet for the hydrogen bromide evolution.Bromine (406 mmol, 64.80 g) was added dropwise to the stirred mixture over a period of 2 h in ice cold conditions.Then, the reaction mixture was warmed to room temperature.After the mixture rested overnight, it was heated at 50 • C for 24 h, washed with a 2N sodium hydroxide solution, refluxed for 7 h with a solution of 8.0 g of potassium hydroxide in 150 mL of 95% ethanol, and poured into water.The organic layer was separated, washed with water, dried over Na 2 SO 4 , and solvent evaporation gave the titled compound as a light-yellow solid (32 g, 75% yield). 1 H-NMR (CDCl 3 , 200 MHz): 6.90 (s, 1H).
3.2.Synthesis of (3,5-Dibromothiophen-2-yl)methanol 3 2,3,5-Tribromothiophene 2 (93 mmol, 30 g) and 300 mL of dry THF were taken in 500 mL of a round bottom flask and cooled to −78 • C. A total of 66 mL of n-BuLi (1.1 equiv., 1.6 M in hexane) was added slowly to the reaction mixture over a period of 10 min and the mixture was stirred for 30 min at the same temperature.Then, 18.0 g of DMF was added slowly to the reaction mixture and stirred at −78 • C for 30 min.It was warmed to 0 • C and quenched with saturated NH 4 Cl solution.The reaction mixture was extracted with EtOAc, dried with Na 2 SO 4 , and concentrated to obtain a light-yellow liquid.A total of 100 mL of THF was added to it and the reaction mixture was placed at 0 • C.An amount of 8 mL of methanol was added and then 6 g of NaBH 4 was added portion-wise.After being stirred for 20 min at room temperature, the reaction mixture was quenched with NH 4 Cl and extracted with EtOAc.The organic layer was washed with brine and dried over Na 2 SO 4 .Concentration and flash column chromatography (ethyl acetate/hexane) gave the titled compound as a light-yellow liquid (19.2 g, 78% yield). 1 H-NMR (CDCl 3 , 200 MHz): 6.91 (s, 1H), 4.72 (s, 2H), 1.98 (bs, 2H).

Conclusions
This protocol utilizes the chemo-and regioselective Br/Li exchange reaction to generate multi-functionalized thiophene, which can then be utilized for further derivation with numerous applications.Specifically, up to 5 g of 5-propyl-2-((trityloxy)methyl)thiophene-3-carbaldehyde was synthesized from thiophene in only 5 steps with an overall yield of 33%.

Supplementary Materials:
The following are available online: Figure S1: 1 H-NMR spectrum of compound 2; Funding: This research received funding from DST, New Delhi, India.