Room Temperature One-Pot Green Synthesis of Coumarin-3-carboxylic Acids in Water: A Practical Method for the Large-Scale Synthesis

Abstract

A simple, facile and convenient practical method for the room temperature one-pot synthesis of a series of potentially biologically active coumarin-3-carboxylic acids has been developed in water from the Knoevenagel condensation and intramolecular cyclization of diverse 2hydroxybenzaldehydes with Meldrum's acid using either potassium carbonate or sodium azide as commercially available, cheap and eco-friendly catalyst. The salient features of the present protocol are mild reaction conditions, good to excellent yields, high atom-economy, environmentally benignity, easy isolation of products, without column chromatography, clean reaction profiles and applicability towards large-scale synthesis.General. Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) FT-IR spectrophotometer using KBr disc. 1 H and 13 C NMR spectra were obtained at 400 MHz and 100 MHz respectively, using Bruker DRX-400 spectrometer and DMSO-d 6 as the solvent.Mass spectra (TOF-MS) were measured on a QTOF Micro mass spectrometer. Elemental analyses were performed with an Elementar Vario EL III Carlo Erba 1108 micro-analyzer instrument. X-ray data were collected on a Bruker single crystal X-ray difractometer (model:APEX 2). Melting point was recorded on a Chemiline CL-726 melting point apparatus and is uncorrected. Thin Layer Chromatography (TLC) was performed using silica gel 60 F 254 (Merck) plates. General procedure for the synthesis of coumarin-3-carboxylic acids (3): An oven-driedscrew cap test tube was first charged with a magnetic stir bar, salicylaldehydes (1, 1.0 mmol), Meldrum's acid (2, 1.0 mmol; 144 mg), distilled water (5 mL) and K 2 CO 3 (20 mol%; 28 mg).The whole mixture was then stirred vigorously at room temperature (24-26 ο C) for 20 h to complete the conversion. Upon completion, the resulting solution was acidified with chilled acid-water, when solid mass precipitated out, filtered off and thoroughly washed with water to obtain almost pure product of coumarin-3-carboxylic acids 3. For further purification, the products were crystallized from ethyl acetate. All the products 3 were also synthesized repeating the same reaction using sodium azide (50 mol%; 33 mg) as the catalyst in place of potassium carbonate. The structure of each purified product was confirmed by its analytical as well as spectral studies including FT-IR, 1 H NMR, 13 C NMR and TOF-MS. For few entries, 2D-NMR ( 1 H-1 H COSY, HMQC and HMBC) spectral properties were also studied.In addition, single X-ray crystallographic studies for one entry, 6-methoxycoumarin-3carboxylic acid (3f), was performed.

Design for carbon–carbon bond forming reactions under ambient conditions

“…An aromatic aldehyde substrate (5; an electron-rich guest) first became efficiently encapsulated into the host's (cage-A) hydrophobic cavity, which after then attacked by the enolate of Meldrum's acid (58) to generate oxyanion intermediate. 160 The present method is not only cost-effective and environmentally benign, but also experimentally safe and simple, easy to handle, clean, and efficient also for the large-scale synthesis eliminating the use of any toxic organic solvent and tedious operation of column chromatographic purification. The eventual loss of water molecule occurs smoothly within the hydrophobic cavity to form the dehydrated product (59) which is too large for the cavity and is spontaneously released from the cage, and a new incoming substrate molecule (5) occupies the position.…”

“…[283][284][285][286][287][288] Huang et al 289 successfully demonstrated the ring-expansion reaction of bicyclic vinylidenecyclopropanes (160) in the presence of titanium chloride (TiCl 4 ) as a Lewis acid catalyst in dichloromethane, providing an efficient method for the synthesis of naphthalenes with annulated carbocycles of various ring sizes (161) in good to excellent yields under mild conditions at room temperature (Scheme 57). [283][284][285][286][287][288] Huang et al 289 successfully demonstrated the ring-expansion reaction of bicyclic vinylidenecyclopropanes (160) in the presence of titanium chloride (TiCl 4 ) as a Lewis acid catalyst in dichloromethane, providing an efficient method for the synthesis of naphthalenes with annulated carbocycles of various ring sizes (161) in good to excellent yields under mild conditions at room temperature (Scheme 57).…”

Ceric Ammonium Nitrate (CAN): An Efficient and Eco‐Friendly Catalyst for One‐Pot Synthesis of Diversely Functionalized Biscoumarins in Aqueous Medium under Ambient Conditions

“…Coumarin (2‐oxo‐2 H ‐1‐benzopyran), a ‘privileged’ O ‐heterocyclic structural motif, is very much well‐known for its diverse range of useful pharmacological profiles . A biscoumarin, generated upon tethering of two such coumarin units through a bridge, may thus invoke to exhibiting somewhat extended and unique biological properties.…”

“…Coumarin (2-oxo-2H-1-benzopyran), a 'privileged' O-heterocyclic structural motif, is very much well-known for its diverse range of useful pharmacological profiles. [1] A biscoumarin, generated upon tethering of two such coumarin units through a bridge, may thus invoke to exhibiting somewhat extended and unique biological properties. Encouraged with this view, researchers already explored a good deal of biscoumarin derivatives, both natural and synthetic, and evaluated for their multifaceted pharmacological applications including anticoagulant, [2] antioxidant, [3] anticancer, [4] enzyme inhibitory activity, [5] antimicrobial, [4f] and many more.…”

Rapid and Efficient Uncatalyzed Knoevenagel Condensations from Binary Mixture of Ethanol and Water

“…In the earliest works, the amines used to catalyze the reactions presented a considerable level of toxicity. 16,17 Thus, many papers have been published in recent years concerning proposals for ecofriendly reaction conditions, [18][19][20][21][22] in accordance with the principles of green chemistry. [22][23][24][25] From this perspective, many researchers have developed new catalysts involving the mentioned principles.…”