News Column

Patent Issued for Microwave Induced Single Step Green Synthesis of Some Novel 2-Aryl Aldehydes and Their Analogues

July 30, 2014



By a News Reporter-Staff News Editor at Journal of Engineering -- According to news reporting originating from Alexandria, Virginia, by VerticalNews journalists, a patent by the inventors Sinha, Arun Kumar (Himachal Pradesh, IN); Sharma, Abhishek (Himachal Pradesh, IN); Kumar, Rakesh (Himachal Pradesh, IN); Sharma, Naina (Himachal Pradesh, IN), filed on February 25, 2010, was published online on July 15, 2014.

The assignee for this patent, patent number 8779200, is Council of Scientific & Industrial Research (New Delhi, IN).

Reporters obtained the following quote from the background information supplied by the inventors: "The 2-aryl aldehyde constitutes an immensely important synthon for the synthesis of various commercially and pharmacologically valuable compounds. For instance, the commercially important non steroidal anti-inflammatory drugs like naproxen (2-(6'-methoxy-2'-naphthyl)-propionic acid) and ibupfren (2-(4'-isobutylphenyl)-propionic acid) are alpha aryl alkanoic acids and their analogues which are synthesized through various synthetic approaches including the oxidation of corresponding 2-aryl aldehydes (C. Commun. 2007, 1739-1741; J. Org. Chem. 1999, 64, 5029-5035, Organometallics 10, 1183-1189, 1991, 1183, WO 9303839). In particular, naproxen has been widely recognized as an ace anti-inflammatory agent and ranked fourth in sales in the global pharmaceutical market in 1991. Similarly ibupfren is a well known anti-inflammatory drug which has been converted from ethical (prescription) to the counter status. Besides their synthesis using 2-aryl aldehydes as intermediates, the above 2-aryl alkanoic acids have also been synthesized from various other approaches, principal amongst them being the carbonylation of respective arylethyl alcohols (Japanese Kokai patent No SHO 55 (1980)-27147), electrocarboxylation of corresponding aryl methyl ketones (U.S. Pat. No. 4,601,797, Japanese patent J60100536, J60103193 and EP-A-189120), or carbonylation of secondary benzyl halides (J. Organometallic chemistry 282, (1985) 277-282, U.S. Pat. No. 4,536,595, EP Nos. 76721, 76722, or by the coupling of alpha-halopropionic acid with 2-(6-methoxynaphthyl) copper (U.S. Pat. No. 3,658,863), zinc (U.S. Pat. No. 3,663,584), cadmium (U.S. Pat. Nos. 3,658,858 and 3,694,476) or coupling of aryl magnesium halides with potassium 2-iodopropionate (German OLS No. 2145650) or reaction of aryl Grignard reagent with lithium, sodium, magnesium salts of 2-bromopropionic acids (U.S. Pat. No. 3,959,364) or carbonylation of aryl halide with CO and cobalt catalyst (U.S. Pat. No. 3,974,202), Palladium catalyst (U.S. Pat. No. 4,713,484) or by the arrangement of alpha-haloketals in the presence of a lewis acid (EP No. 0034871).

"However, all above methods suffer from one or the other limitations like multistep synthesis, use of expensive and hazardous organometallic agents besides the problems in maintenance of high CO pressure.

"In view of the above concerns, there have been continuing efforts to develop alternative synthetic approaches towards the immensely important 2-aryl alkanoic acid framework. In this context, the synthesis of 2-aryl alkanoic acids through the respective 2-aryl aldehydes as a useful synthon constitutes a simple and straight forward procedure which has been described in the prior art (C. Commun. 2007, 1739-1741, J. Org. Chem. 1999, 64, 5029-5035, Organometallics 10, 1183-1189 1991, WO 9303839).

"In addition to their above usefulness as critical intermediates for the synthesis of commercially important anti-inflammatory drugs, the various other 2-aryl aldehyde analogues and especially the 2,2-diaryl aldehydes have recently been found to be privileged structural motifs for accessing some new potent anticancer compounds (U.S. Pat. No. 6,943,194 B1, J. Org. Chem. 1996, 65, 7438-7444). In particular, the above prior art discloses the formation of some novel trimethoxystilbene based benzophenone derivatives namely hydroxy phenstatin which showed potent inhibition of tubulin assembly (IC.sub.50=0.82 .mu.M) and exhibited an ED.sub.50 of 0.25 .mu.g/ml against the P388 lymphocytic leukemia cell lines, thus establishing their potent antitumor and antimitotic credentials. In the light of above discussion, it would be clear that a putative stilbene based benzophenone scaffold holds immense potential for displaying useful medicinal properties including anticancer activities. However, the synthesis of above medicinally important compounds themselves depend on the availability of critical synthons including the corresponding 2,2-diaryl aldehydes as evident in the prior art (U.S. Pat. No. 6,943,194 B1, J. Org. Chem. 1996, 65, 7438-7444). It is also evident that the various 2-aryl aldehydes and analogues such as 2,2-diaryl aldehydes constitute a privileged class of compounds with diverse applications for the synthesis of commercially and medicinally important compounds. However, the development of a convenient and economical protocol for the synthesis of above synthon i.e. 2-aryl aldehydes from easily available substrates like aryl alkenes has in itself remained tedious and expensive proposition. For instance, Organometallics 1991, 10, 1183-1189 discloses a method for multistep synthesis of 2-aryl aldehydes from the corresponding aryl ethenes utilizing expensive and hazardous reagents like rhodium catalyst and BINAPHOS ligand.

"Similarly, J. Org. Chem. 1997, 62, 6547-6561 discloses a method for the formation of 2-aryl and 2,2-diaryl aldehydes via a multistep methodology involving the formation of epoxide from aryl alkene and its subsequent rearrangement using toxic palladium catalyst and phosphine ligands.

"Similarly, J. Org. Chem. 1998, 63, 8212-8216 discloses a multistep method for the formation of 2-aryl and 2,2-diaryl aldehydes from respective aryl alkenes via the rearrangement of an intermediate epoxide using rare and expensive InCl.sub.3 as a lewis acid.

"In yet another instance, 2-aryl aldehydes were synthesized via the rearrangement of epoxides obtained from the corresponding aryl alkenes using lithium perchlorate as a lewis acid catalyst (J. Org. Chem. 1996, 61, 1877-1879).

"Similarly, the 2-aryl and 2,2-diaryl aldehydes were synthesized via the rearrangement of corresponding epoxides using expensive IrCl.sub.3 as a lewis acid catalyst (Tetrahedron Lett. 44, 2003, 7687-7689).

"In a Similar manner, J. Org. Chem. 1996, 65, 7438-7444 discloses the multistep formation of 2,2-diaryl aldehydes from the corresponding stilbenes using boron trifluoride etherate catalyst.

"In another instance, 2-aryl aldehydes were synthesized from the corresponding aryl alkenes, however, the methodology required an indispensable usage of base catalyst in the form of hazardous heavy metal salts like silver oxide etc. which precludes its use in case of substrates containing base sensitive groups. (Chem. lett. 1984, 341-344). In addition, the above methodology might also lead to production of corresponding carboxylic acids, as undesired side product, due to the known tendency of silver oxides for such a transformation (Tetrahedron: Asymmetry, 2005, 16, 1837-1843).

"In view of the above, it is quite apparent that there has been a dearth of convenient protocols for the direct synthesis of 2-aryl aldehydes and analogues such as 2,2-diaryl aldehydes from corresponding arylalkenes as almost all the prevalent methods utilize multiple steps involving an intermediate epoxide besides the use of toxic, rare, and expensive transition metal/organometallic catalysts.

"Thus, it becomes an object of the present invention to develop a convenient, economical and environment friendly synthetic methodology which not only provides the highly valuable 2-aryl and 2,2-diaryl aldehydes from the corresponding aryl alkenes in a single step but also simultaneously eliminates the hitherto indespensible requirement of expensive and hazardous transition metal catalysts."

In addition to obtaining background information on this patent, VerticalNews editors also obtained the inventors' summary information for this patent: "The present invention provides a process for the preparation of 2-aryl aldehydes and analogues which are critical intermediates both for the synthesis of commercially important anti-inflammatory drugs like naproxen and medicinally important potent anticancer compounds like phenstatin and many others in a single step under microwave irradiation by reaction of the corresponding aryl alkene with N-halosuccinimide in the presence of a phase transfer catalyst and solvent. N-halosuccinimide used is selected from the group consisting of N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide and the like. Solvent for the process is selected from a group consisting of dimethyl sulphoxide, dimethylformamide, dimethoxyethane, ionic liquids and the like. The final product i.e. 2-aryl aldehydes and analogues are obtained in good to moderate yields varying from 35-55% within 1 min-16 hrs depending upon the substrate and reagent mixture. It is worthwhile to mention that this microwave-assisted unique process in fact represents a novel, economical and environment friendly approach for the direct synthesis of highly valued 2-aryl aldehydes and analogues from corresponding aryl alkenes under aqueous conditions without the use of hitherto indispensable, expensive and hazardous transition metal catalysts.

"Accordingly, the present invention provides novel 2-aryl aldehydes of the general formula 1:

"##STR00001## wherein, R' is selected from CH.sub.3, C.sub.2H.sub.5, C.sub.6H.sub.5 or C.sub.6H.sub.4-(4'-OCH.sub.3); X represents O or N--NH--SO.sub.2--C.sub.6H.sub.4--CH.sub.3; the substituents amongst R.sub.1 to R.sub.5 are selected from a group consisting of H, OH, OCH.sub.3, C.sub.6H.sub.5, halogen atom or R.sub.2+R.sub.3 together represent (CH.dbd.CH--CH.dbd.CH) group or (O--CH.sub.2--O) group and R.sub.1, R.sub.4, R.sub.5 are selected from a group consisting of H, OH, OCH.sub.3, C.sub.6H.sub.5, halogen atom;

"In another embodiment of the present invention, the representative compounds of the general formula 1 comprising: (i) 2-(2,4,5 trimethoxy phenyl)propionaldehyde; (ii) 2-(2,4,5 trimethoxy phenyl)propionaldehyde tosyl hydrazone; (iii) 2-(1-naphthyl)-butylaldehyde; (iv) 2-(2-bromo-3,4-dimethoxyphenyl)propionaldehyde; (v) 2-(2-bromo-3,4-dimethoxyphenyl)propionaldehyde tosyl hydrazone; (vi) 2-(4-hydroxy, 3-methoxyphenyl)-2-(4'-methoxyphenyl)acetaldehyde.

"In yet another embodiment of the present invention, a microwave induced single step synthesis of 2-aryl aldehydes and analogues of general formula 1, wherein the said process comprising the steps of: a) reacting substituted aryl alkene and N-halosuccinimide and a phase transfer catalyst in a solvent under conventional or microwave irradiation; b) transferring the reaction mixture of step (a) into ice cold water and extracting with an organic solvent; c) washing the organic solution of step (b) with aqueous sodium thiosuphate, brine and water, d) drying the organic layer of step over anhydrous sodium sulphate, 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 1:10 to 4:6 mixture of ethylacetate and hexane to obtain the required substituted 2-aryl aldehydes of general formula 1.

"In yet another embodiment of the present invention, the N-halosuccinimide used is selected from the group consisting of N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide or a combination thereof.

"In still another embodiment of the present invention, the solvent used in step (a) is either water or a mixture of water-organic solvent wherein the organic solvent is selected from the group consisting of dimethyl sulphoxide, dioxane, dimethylformamide, dimethoxyethane, ionic liquids or a combination thereof.

"In still another embodiment of the present invention, the phase transfer catalyst is selected from a group consisting of CTAB, CTAC or various chiral phase transfer catalysts such as N-benzylcinchonidinium chloride.

"In still another embodiment of the present invention, the developed process is applied equally successfully on aromatic ring in aryl alkenes.

"In yet another embodiment the organic solvent used in step (b) is ethyl acetate.

"In yet another embodiment of the present invention, the claimed process is found workable in both a monomode and a multimode microwave.

"In yet another embodiment of the present invention, the reaction is performed in a monomode microwave organic synthesizer operated at 50-300 W power level with 120-200.degree. C. for 1-45 min, irradiation frequency used is in the range of 900 to 3000 MHz, more preferably in the range of 2450 to 2455 MHz.

"In furthure another embodiment of the present invention, the mole ratio between substituted arylalkene and N-halosuccinimide is ranging between 1:1 to 1:3 moles.

"In still furthure another embodiment of the present invention, the volume ratio of water and organic solvent is in the range of 1:4 to 4:1, preferably being 3:1.

"In still another embodiment of the present invention, the mole ratio between the substituted arylalkene and phase transfer catalyst is ranging between 1:0.1 to 1:0.5 moles.

"In still yet another embodiment of the present invention, halohydrin formation and subsequent rearrangement to 2-aryl aldehydes from corresponding aryl alkanols occur in the same pot without the formation of an intermediate epoxide or use of a transition metal catalyst, lewis acid/base.

"In still yet another embodiment of the present invention, the claimed process can be used for the preparation of 2-aryl aldehydes, 2,2-diaryl aldehydes and analogues which are important intermediates for commercially important nonsteroidal anti-inflammatory drugs and some medicinally important potent anticancer compounds by taking different substrates.

"In still another embodiment of the present invention, the use of chiral phase transfer catalyst provides asymmetric access towards chiral 2-aryl aldehyde."

For more information, see this patent: Sinha, Arun Kumar; Sharma, Abhishek; Kumar, Rakesh; Sharma, Naina. Microwave Induced Single Step Green Synthesis of Some Novel 2-Aryl Aldehydes and Their Analogues. U.S. Patent Number 8779200, filed February 25, 2010, and published online on July 15, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8779200.PN.&OS=PN/8779200RS=PN/8779200

Keywords for this news article include: Acyclic Hydrocarbons, Aldehydes, Alkenes, Emerging Technologies, Nanotechnology, Organic Chemicals, Organometallic Organosol.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


For more stories covering the world of technology, please see HispanicBusiness' Tech Channel



Source: Journal of Engineering


Story Tools






HispanicBusiness.com Facebook Linkedin Twitter RSS Feed Email Alerts & Newsletters