Patent Issued for One Pot Multicomponent Synthesis of Some Novel Hydroxy Stilbene Derivatives with
The assignee for this patent, patent number 8716532, is
Reporters obtained the following quote from the background information supplied by the inventors: "Stilbene and its derivatives have been widely reported to possess a plethora of industrial and pharmaceutical applications. In particular, the hydroxy substituted stilbenoids have been found to be privileged structural motifs in diverse bioactive natural products. For instance, various dihydroxy stilbene derivatives based on lithospermic acid, a polyphenolic compound found in Salvia miltorrhiza (Planta Med. 1984; 50, 227-228, Phytochemistry 1994, 37, 907-908) have been implicated as potent antidiabetic agents as they display significant inhibitory activity against protein tyrosine phosphatase (PTP1B) enzyme (Bioorg. Med. Chem. Lett. 2007, 17, 4481). Similarly, the salvionolic acid derivatives, isolated from genus Salvia, have been widely studied and ascribed numerous biological activities including antitumoral, anti-inflammatory, gastric and antioxidant activities (US 2003/0086987A1 and US 2002/0197274A1). In yet another instance, the multiconjugated stilbenes like 1,4-bis-styrylbenzenes are reported to possess important applications as in vivo magnetic resonance imaging agents for diagnosis and monitoring of various neurodegenerative ailments like Alzheimer's disease owing to their strong amyloid fibril (A.beta.) plaque binding ability (J. of Med. Chem., 2007, 50, 4986). In addition, the 1,4-bis-styrylbenzenes have also been used as optical brighteners (U.S. Pat. No. 4,371,475). Similarly, resveratrol, a phytoalexin, present in grapes and other fruits (
"Various other commercially important stilbene derivatives have been accessed through diverse reaction methodologies, including Wittig, modified
"The following prior art references are disclosed as below:
"Some of other typical prior art references include U.S. Pat. Nos. 6,844,471, 6,552,213, 20040152629 A1; 6361815; 5569786; European Pat. Nos. EP 0331983; Tetrahedron lett., 1980, 21, 2073; Synthesis, 1977, 58,
"Amongst the above mentioned synthetic methodologies for hydroxy stilbenes, the palladium catalysed Heck reaction between hydroxy styrenes and halobenzenes has remained a prominent approach due to the easy availability of variously substituted halobenzenes, remarkable ability of palladium catalyst to withstand a wide range of functional groups coupled with the possibilty to conduct multicomponent reactions using appropriately substituted reactants. However, the Heck approach for hydroxy substituted stilbenes has also been recognized to be tedious and inefficient due to the preponderant tendency of hydroxy styrenes for polymerization. Consequently, a majority of the prevalent Heck approaches for hydroxy stilbenes comprise multistep protection-deprotection sequences (
"In order to address the above concerns, it therefore, becomes an object of the invention to develop a method, wherein the hydroxy styrenes are formed from the corresponding benzaldehydes, cinnamic acids or their derivatives and then allowed to react in situ with appropriately substituted halobenzenes under Heck like conditions to give the desired stilbene derivatives without any need for isolation of reaction intermediates or protection-deprotection steps. The above one pot approach would not only remove the currently indispensable and synthetically inefficient isolation of reaction intermediates obtained from sequential condensation, decarboxylation and Heck reactions but also provide the desired stilbenes in enhanced yields as it would allow the hydroxystyrenes to in situ join the desired Heck coupling pathway instead of the competing wasteful polymerization pathways.
"It is worthwhile to mention that we had earlier disclosed a microwave induced process for the preparation of substituted stilbenes and its analogs (U.S. Patent No. 20070276172 A1). However, the above approach employing Perkin reaction between hydroxy benzaldehydes and phenyl acetic acids was limited towards the synthesis of stilbenes (C.sub.6--C.sub.2--C.sub.6 chain) possessing a single ethylinic linkage which severely precluded an access towards immensely important multiconjugated stilbenes possessing an .alpha., .beta.-unsaturated carboxylic acid moiety i.e. (C.sub.6--C.sub.2--C.sub.6--C.sub.3 chain). In contrast, such an introduction of extra C.sub.3 chain to stilbene moiety (C.sub.6--C.sub.2--C.sub.6 chain) is not possible using our above patent (U.S. Patent No. 20070276172 A1). Further, the present invention not only gives a new one pot approach towards Heck coupling of in situ formed hydroxy styrenes, but also provides an unprecedented opportunity to conduct simultaneous multicomponent reactions in one pot leading to a novel single step synthesis of a range of medicinally important multiconjugated stilbene derivatives including antidiabetic lithospermic acids etc. which had hitherto been accessed only through tedious multistep protocols.
"In view of the above discussion, it is quite evident that there is a need for developing efficient synthetic protocols for hydroxy substituted stilbene derivatives and analogues in view of the current limitations like lengthy mutistep protocols, use of harsh protection-deprotection reagents and low yields of final products etc. It, therefore, becomes an object of the invention to provide a rapid, economical and one pot multicomponent process for the preparation of 2- or 4-hydroxy substituted stilbene derivatives from cheap and commercially available substituted arylaldehydes and halobenzenes so as to eliminate the disadvantages associated with the above patents and papers. It is worthwhile to mention that microwave-assisted (
"Keeping in view the above problems, we disclose a unique and novel one pot process to prepare 2- or 4-hydroxystilbene derivatives and their analogues in one step from 2- or 4-hydroxy substituted arylaldehydes, malonic acid and halobenzenes in the presence of a base, palladium catalyst, triphenylphosphine and solvent. In fact, we have already observed that while trying to emulate Knoevenagel Doebner condensation (
In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention provides a process for the preparation of some novel commercially important multiconjugated 2- or 4-hydroxy substituted stilbene derivatives such as analogues of lithospermic acid, bis-styrylbenzenes, salvianolic acid, resveratrol, pterostilbene, and many others under microwave irradiation from the one pot multicomponent reaction of substituted arylaldehydes, malonic acid and halobenzenes with at least one hydroxy substituent at 2- or 4-position of arylaldehyde in the presence of a base, Pd catalyst, PPh.sub.3 and solvent. The base is selected from a group consisting of collidine, triethylamine, pyridine, piperidine, sodium acetate, ammonium acetate, imidazole, methyl imidazoles, DBU and the like. Palladium catalyst is selected from a group consisting of palladium acetate, palladium nanoparticles, palladium chloride, tetrakis(triphenylphosphine)palladium(0) etc. Solvent for the process is selected from a group consisting of dimethylformamide, polyethylene glycol, dimethoxyethane, glycol, NMP, DMA, toluene, pyridine, ionic liquids and the like. The final products 2- or 4-hydroxy substituted stilbene derivatives are obtained in good to moderate yields varying from 25-66% within 1 min-16 hrs. It is worthwhile to mention that this microwave-assisted unique process is in fact an unexpected and novel result of three-four individual steps consisting of condensation of substituted arylaldehydes and malonic acid, decarboxylation and coupling of hydroxy styrene with halobenzenes occurring in one pot with at least one hydroxy substituent at 2- or 4-position of arylaldehyde without addition of any decarboxylating or protection-deprotection agents. It is also important to note that the developed one pot multicomponent process provides 2- or 4-hydroxy substituted stilbene derivatives in enhanced yields and reduced times in comparison to when the same reactions are conducted separately through the sequential isolation of reaction intermediates. Further that conducting the above reaction by conventional method instead of microwave provides the corresponding cinnamic acids as major products and low yield of stilbene derivatives, even when 2- or 4-hydroxy substituted arylaldehyde are taken as starting materials.
"Accordingly, the present invention provides novel multiconjugated hydroxy stilbene derivatives with the general formula 1:
"##STR00001## wherein, at least one substituent being OH amongst R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.10, and rest of substituents amongst R.sub.1 to R.sub.10, being H, OH, OCH.sub.3, CH.sub.3COO, halogen group, nitro group, CH.dbd.CH--COOH, C.sub.6H.sub.3 -(4-OH,3-OMe), C.sub.6H.sub.4--CH.dbd.CH--CO--C.sub.6H.sub.4-(4-OMe), CH.sub.2--CH.sub.2--CH.sub.3 or combinations thereof.
"In an embodiment of the present invention, the representative compounds of the general formula 1 comprising; i. 4-((E)-prop-2-enoic acid)-3',4'-dihydroxystilbene, ii. 4-((E)-prop-2-enoic acid)-4'-hydroxy-3',5'-dimethoxystilbene, iii. 2'-(propyl)-4-hydroxy-3,4',5'-trimethoxystilbene, iv. 4-hydroxy-3,4',5-trimethoxy stilbene, v. 4-hydroxy-3-methoxy, 3'4'-dioxymethylenestilbene, vi. 2-(4-hydroxy-3-methoxystyryl)thiophene, vii. (E,E)-1,4-Bis(4-hydroxy, 3-methoxy)styrylbenzene, viii. ((E,E)-1,4-Bis(4-hydroxy-3-methoxy)styrylbenzene, ix. ((E,E)-1,4-Bis(4-hydroxy-3,5-dimethoxy)styrylbenzene, x. ((E,E)-4,4'-Bis(4-hydroxy-3,5-dimethoxy)styrylbiphenyl, xi. ((E,E,E)-1,3,5-
"In another embodiment of the present invention, the said process comprising the steps of: a) reacting substituted arylaldehyde with at least one hydroxy substituent at 2- or 4-position, malonic acid and halobenzene in the presence of a base, palladium catalyst, triphenylphosphine and a solvent by refluxing under conventional or microwave irradiation for a period ranging between 30 min-15 hr. b) transferring the reaction mixture of step (a) and washing the residue with an organic solvent, c) washing the organic solution of step (b) with a mineral acid, brine and water, d) drying the organic layer of step © over a dehydrating agent, filtering and evaporating to dryness to completely remove the solvent to obtain a residue, e) purifying the residue of step (d) on Si-gel (60-120 mesh size) with a mixture of ethylacetate and hexane (9:1 to 6:4) to obtain the required substituted 2-aryl aldehydes of general formula 1.
"In yet another embodiment of the present invention, the base used is selected from the group consisting of collidine, triethylamine, pyridine, piperidine, DBU, sodium acetate, ammonium acetate, imidazole, methyl imidazoles, ammonium formate and a combination there of.
"In yet another embodiment of the present invention, the palladium catalyst used is selected from the group consisting of palladium acetate, palladium nanoparticles, to palladium chloride, tetrakis(triphenylphosphine)palladium(0) and a combination there of.
"In still another embodiment of the present invention, the solvent used is selected from the group consisting of dimethylformamide, polyethylene glycol, dimethoxethane, NMP, DMA, toluene, pyridine, ionic liquids and a combination there of.
"In still another embodiment of the present invention, the mole ratio between substituted arylaldehyde and malonic acid is ranging between 1:1 to 1:4 moles.
"In still yet another embodiment of the present invention, the mole ratio between the substituted arylaldehyde and the base is ranging between 1:1 to 1:6 moles, preferably, 1:3 moles.
"In still yet another embodiment of the present invention, the mole ratio between the substituted arylaldehyde and halobenzene is ranging between 1:1 to 1:2 moles.
"In further yet another embodiment of the present invention, the mole ratio between halobenzene and palladium catalyst is ranging between 1:0.01 to 1:0.04 moles.
"In further another embodiment of the present invention, the mole ratio between halobenzene and triphenylphosphine is ranging between 1:0.01 to 1:0.05 moles.
"In further another embodiment of the present invention, the claimed process is found workable in both monomode at 250 W and 160.degree. C. temperature and multimode microwave at 700-1500 W and 160-180.degree. C. temperatures.
"In yet another embodiment of the present invention, the various substituted stilbene derivatives obtained by the developed process can also be hydrogenated in same pot to provide the biologically important bibenzyl derivatives.
"In yet another embodiment of the present invention, the hydroxylated or methoxylated styrenes obtained in situ via decarboxylation of respective cinnamic acid derivatives also undergo multicomponent reaction of hydroxy substituted benzaldehydes in the same pot in the presence of an ionic liquid.
"In further another embodiment of the present invention, the process for the preparation of 2- or 4-hydroxy substituted stilbene derivatives is carried out in a one pot multicomponent manner wherein condensation, decarboxylation and heck coupling occur simultaneously without either the need for decarboxylating/protection-deprotection agents or individual isolation of highly reactive intermediates in one step."
For more information, see this patent: Sharma,
Keywords for this news article include: Anions, Therapy, Styrenes, Chlorides, Palladium, Legal Issues, Nanoparticle, Benzaldehydes, Nanotechnology, Hydrochloric Acid, Benzene Derivatives, Transition Elements, Emerging Technologies.
Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC
Most Popular Stories
- 'Lucy's' Super Powers Tops 'Hercules' at Box Office
- The 2014 Fastest-Growing 100
- Vancrest Assisted Living Project to Add 20 Jobs
- Fighting Blocks Investigators, Police From MH17 Crash Site
- The Rise and Fall of Richard Alarcon
- VW Site Could Mean Another 2,000 Jobs for Chattanooga
- Ford Bumps Price of New F-150
- Insecticides Permeate U.S. Food, Water Supply
- Nissan Profits Rise on Growth in U.S., China
- U.N. Renews Demand for Gaza Cease-Fire