Patent Application: US-83503810-A

Abstract:
ruthenium nanoparticles supported on non - cross - linked soluble polystyrene were prepared by reacting ] 2 with polystyrene in open air . they effectively catalyze intra - and intermolecular carbenoid insertion into c — h and n — h bonds , alkene cyclopropanation , and ammonium ylide /- sigmatropic rearrangement reactions . this supported ruthenium catalyst is much more reactive than ] 2 and ruco ] for catalytic intermolecular carbenoid c — h bond insertion into saturated alkanes . by using a - diazoacetamide as a substrate for intramolecular carbenoid c — h insertion , the supported ruthenium catalyst can be to recovered and reused for ten successive iterations without significant loss of activity .

Description:
the present invention relates to the use of non - cross - linked soluble polystyrene supported ruthenium nanoparticles for practical carbenoid transfer reactions . in a typical example , preparation of the ruthenium nanoparticles catalyst ncps - ru was undertaken by heating a mixture of non - cross - linked polystyrene ncps ( 0 . 50 g ) and [ rucl 2 ( c 6 h 5 co 2 et )] 2 ( 0 . 10 g , 0 . 16 mmol ) in 1 , 2 - dichloroethane ( 30 ml ) in open air at 70 ° c . for 24 h ( scheme 1 ). the solution was concentrated in vacuo . the residue was taken up in 5 ml of 1 , 2 - dichloroethane . this solution was added dropwise to a vigorously stirred cold hexane ( 200 ml ). the black precipitate was filtered and dried to afford ncps - ru as a black powder ( 0 . 58 g , ca 100 %). the ruthenium content of ncps - ru was determined to be 5 . 0 % w / w using inductively coupled plasma spectroscopy ( icp ), and hence the loading was 0 . 50 mmol / g . similarly , other soluble polymer supports such as poly ( tert - butylstyrene ) ( ncptbs ), poly ( tert - butylstyrene - co - styrene ) ( ncptbs - co - ps ), and poly ( n - isopropylacrylamide - co - styrene ) ( pnipam - co - ps ) were used to react with [ rucl 2 ( c 6 h 5 co 2 et )] 2 in 1 , 2 - dichloroehtane to give the corresponding soluble polymer - supported ruthenium catalysts as depicted in fig1 . examination of ncps - ru by transmission electron microscopy ( tem ) showed the presence of well - dispersed spherical ruthenium nanoparticles ( fig2 a ) with the average diameter and monodispersity being 1 . 72 ± 0 . 17 nm and 9 . 9 %, respectively ( fig2 b ). selected area electron diffraction ( saed ) image showed two broad diffraction rings , which can be indexed back to metallic ruthenium ( jcpds no . 06 - 0663 ) ( fig2 c ). high resolution tem imaging showed clear lattice fringes revealing that the nanoparticles were single - crystallized ( fig2 d ). the d - spacing of the particle was 2 . 047 å corresponding to the ( 101 ) plane of metallic ruthenium . x - ray photoelectron spectroscopic ( xps ) analysis of a freshly prepared ncps - ru catalyst showed a peak at 463 . 9 ev corresponding to ru 3p 3 / 2 binding energy ( see fig3 ). this value slightly deviated from the reported value of bulk ruthenium metal ( 462 . 0 ev ) [ j . f . moulder , w . f . stickle , p . e . sobol , k . d . bomben is in handbook of x - ray photoelectron spectroscopy ( eds . : j . chastain , r . c . king ), physical electronic , eden prairie , 1995 ], revealing that the polymer supported ruthenium nanoparticles might contain surface coated oxidized ruthenium ions . the invention further relates to synthesis of cis - β - lactams via intramolecular carbenoid c — h insertion of α - diazoacetamides catalyzed by ncps - ru . a mixture of diazo compound ( 1 . 0 mmol ) and ncps - ru ( 1 . 0 mol %) was stirred in toluene ( 2 ml ) at 70 ° c . the reaction was monitored by tlc analysis ( 20 % etoac - hexane ) for complete consumption of diazo starting material . upon addition of hexane ( 2 ml ) the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantification by 1 h nmr spectroscopy . to obtain a pure product , the supernatant was separated and evaporated to dryness by rotary evaporation , and the residue was loaded onto a silica gel for column chromatography . the substrate scope of the intramolecular carbenoid c — h insertions has been examined and the results are depicted in table 1 . a variety of substrates undergo cyclization in the presence of ncps - ru ( 1 mol %). the stereoselectivity is similar to that of homogeneous [ rucl 2 ( p - cymene )] 2 catalyst ( m . k .- w . choi , w .- y . yu , c .- m . che , org . lett . 2005 , 7 , 1081 ). for example , effective transformation of α - diazoacetamides having different aryl substituents to the corresponding cis - β - lactamshave been achieved in & gt ; 90 % yields ( entries 2 and 3 ). when α - diazoketone was employed as substrate , the ncps - ru - catalyzed intramolecular carbenoid c — h is insertion produced trans - β - lactam exclusively in 93 % yield ( entry 4 ). the carbenoid c — h insertion of n , n - diisopropyl substituted α - diazoacetamide was directed to the methine ) ( 3 ° c .) c — h bond furnishing β - lactam in 89 % isolated yield ( entry 5 ). interestingly , with the α - diazoanilide containing an electron donating group ( ome ) or electron withdrawing group ( no 2 ), only intramolecular carbenoid c — h insertion to the phenyl group was found and the corresponding γ - lactams were isolated in good to excellent yields ( entries 6 and 7 ). the catalysis could be performed in a preparative - scale ( 4 . 0 g substrate ). with 1 mol % ru catalyst , the diazo compounds were completely consumed within 4 h and cis - β - lactam ( 3 . 3 g ) was formed as a 98 % yield in a one - pot reaction . the ncps - ru recovered from the intramolecular carbenoid c — h insertion reactions was mixed with diazo compound ( 1 . 0 mmol ) in toluene ( 2 ml ) at 70 ° c . the reaction was monitored by tlc analysis ( 20 % etoac - hexane ) for complete consumption of diazo starting material . upon addition of hexane ( 2 ml ), the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . the reaction vessel containing the catalyst was recharged with diazo compound and toluene ( 2 ml ) for another consecutive reaction run . the soluble polystyrene supported ncps - ru can be recovered and reused . the results in the recycling of ncps - ru for intramolecular carbenoid c — h insertions is are listed in table 2 . the ncps - ru was subjected to ten successive reuses under identical reaction conditions . the organic product was simply recovered by removing solvent from the filtrate without any further purification . after ten consecutive reactions , the recovered ncps - ru was found to contain 5 . 0 w / w of ruthenium based on icp analysis . this ruthenium content was essentially the same as the initial value , revealing no detectable catalyst leaching over the 10 consecutive reactions . ncps - ru catalyzed intramolecular carbenoid c — h insertion of α - diazo compounds derived from various α - amino acids the invention relates to synthesis of highly functionalized γ - lactams via intramolecular carbenoid c — h insertion of α - diazoacetamides catalyzed by ncps - ru . a mixture of diazo compound ( 1 . 0 mmol ) and ncps - ru ( 1 . 0 mol %) was stirred in toluene ( 2 ml ) at 70 ° c . the reaction was monitored by tlc analysis ( 20 % etoac - hexane ) for complete consumption of diazo starting material . upon addition of hexane ( 2 ml ), the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain pure product , the supernatant was separated and evaporated to dryness by rotary evaporation , and the residue was loaded onto silica gel for column chromatography . highly functionalized γ - lactams can be synthesized through catalytic carbenoid c — h insertion of diazoacetamides derived from amino acids ( c . h . yoon , d . l . flanigan , b .- d . chong , k . w . jung , j . org . chem . 2002 , 67 , 6582 ). the results using ncps - ru as catalyst are depicted in table 3 . treatment of diazoacetamide 5a prepared from l - phenylalanine with ncps - ru as catalyst ( 1 mol %) gave trans , trans - γ - lactam 6a in 89 % yield . ( table 3 , entry 1 ). the trans , trans - stereochemistry was established by 1 h - 1h noesy nmr analysis . similarly , trans , trans - γ - lactam 6b was obtained in 90 % yield using 5b as substrate ( table 3 , entry 2 ). α - diazoacetamide 5c containing an electron donating otbs ether group also underwent ru - catalyzed cyclization to afford a 1 : 1 mixture of diastereomeric bicyclic lactams in 92 % yield ( table 3 , entry 3 ). when the reaction was performed at lower temperature ( 40 ° c . ), a mixture of diastereomers was obtained in an overall yield of 89 % and with a ratio of 7c : 6c = 2 : 1 ( table 3 , entry 4 ). the invention also relates to intermolecular c — h insertion of hydrocarbon with methyl phenyldiazoacetate catalyzed by ncps - ru . a mixture of methyl phenyldiazoacetate ( 1 . 0 mmol ), 1 , 4 - cyclohexadiene ( 2 . 0 mmol ) and ncps - ru ( 1 . 0 mol %) was stirred in toluene ( 2 ml ) at 70 ° c . for 2 h . upon addition of hexane ( 2 ml ), the reaction mixture was centrifuged and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain pure sample of the product , the supernatant liquid was separated and evaporated to dryness by rotary evaporation and the residue was loaded onto a silica gel column chromatography . a mixture of methyl phenyldiazoacetate ( 1 . 0 mmol ), 1 , 4 - cyclohexadiene ( 2 . 0 mmol ) and mcps - ru ( 1 . 0 mol %) was stirred in neat hydrocarbon ( 2 ml ) at 70 ° c . for 12 h . upon addition of hexane ( 2 ml ), the reaction mixture was centrifuged and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain pure sample of the product , the supernatant liquid was separated and evaporated to dryness by rotary evaporation and the residue was loaded onto a silica gel column chromatography . due to its inherent difficulty , intermolecular carbenoid c — h insertion of saturated alkanes is more challenging to accomplish [ c . jia , t . kitamura , y . fujiwara , acc . chem . res . 2001 , 34 , 633 ; v . ritleng , c . sirlin , m . pfeffer , chem . rev . 2002 , 102 , 1731 ], and there has been no example on the use of ruthenium complexes as catalysts for intermolecular carbenoid insertion to saturated alkanes . in this work , we investigated ncps - ru catalyzed intermolecular carbenoid c — h insertion reactions , and the results are depicted in table 4 . the reaction of methyl phenyldiazoacetate with neat cyclohexane in the presence of ncps - ru ( 1 . 0 mol %) afforded the c — h insertion product in 60 % yield . similarly , the ncps - ru catalyzed reaction of methylphenyldiazoacetate with 1 , 4 - cyclohexadiene furnished the c — h insertion product and cyclopropanated product with a ratio of 4 : 1 in 66 % overall yield ( table 4 , entry 2 ). with ethyl benzene , a 1 . 2 : 1 mixture of insertion products were obtained in 63 % overall yield ( table 4 , entry 3 ). [ 15 ] the reaction of indane with methyl to phenyldiazoacetate gave the c — h insertion product 17 as a single isomer in 62 % yield ( table 4 , entry 4 ). with n - hexane as substrate , the secondary ( 18a and 18b ) to primary ( 19 ) c — h insertion products were formed with a ratio of 5 : 1 in 50 % overall yield ( table 4 , entry 5 ). the invention relates to intramolecular cyclopropanation of allyl diazoacetates catalyzed by ncps - ru . to a solution of ncps - ru ( 1 . 0 mol %) in toluene ( 2 ml ) was added dropwise a solution of allyl diazoacetate ( 1 . 0 mmol ) in toluene ( 2 ml ), over 10 h at 70 ° c . after the addition , stirring was continued until all the diazo compounds had been consumed . upon addition of hexane ( 2 ml ) the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain pure product , the supernatant was separated and evaporated to dryness by rotary evaporation , and the residue was loaded onto a silica gel for column chromatography . the ncps - ru catalyst is also active toward intramolecular cyclopropanation of alkenes ( table 5 ). treatment of a variety of allyl diazoacetates with the catalyst led to the corresponding cyclopropyl lactones in good yields after 12 h ( 70 %- 89 %, see table 5 ). the catalyst could be recovered quantitatively by precipitation and filtration . the invention relates to intramolecular tandem ammonium ylide formation /[ 2 , 3 ]- sigmatropic rearrangement reactions catalyzed by ncps - ru . to a solution of ncps - ru ( 1 . 0 mol %) in toluene ( 2 ml ) was added dropwise a solution of diazo compound ( 1 . 0 mmol ) in toluene ( 2 ml ) over 2 h at 50 ° c . after the addition , stirring was continued until all the diazo compounds had been consumed . upon addition of hexane ( 2 ml ) the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain pure product , the supernatant was separated and evaporated to dryness by rotary evaporation , and the residue was loaded onto a silica gel for column chromatography . we have also examined intramolecular tandem ammonium ylide formation /[ 2 , 3 ]- sigmatropic rearrangement reactions . treatment of 8 with ncps - ru 1 ( 1 . 0 mol %) afforded [ 2 , 3 ]- sigmatropic rearrangement product 8a in 92 % yield without any [ 1 , 2 ]- rearrangement product being detected ( table 6 , entry 1 ). this result is comparable to the finding using [ ru ii ( ttp )( co )] as catalyst ( c .- y . zhou , w .- y . yu , p . w . h . chan , c .- m . che , j . org . chem . 2004 , 69 , 7072 ). similarly diazoketone 9 was found to undergo effective cyclization to give pyridone 9a in 89 % yield ( table 6 , entry 2 ) and diazoester 10 was converted to morpholinone 10a in 91 % yield ( table 6 , entry 3 ). previously , we reported that the [ ru ii ( ttp )( co )] to catalyzed intramolecular ammonium ylide /[ 2 , 3 ]- sigmatropic rearrangement could be applied as a key step for the total synthesis of (±)- platynecine . in this work we found that using ncps - ru 1 catalyst ( 1 mol %), a comparable result ( 85 % yield , dr = 2 : 1 ) was obtained ( scheme 2 ). the invention relates to intermolecular cyclopropanation of alkene with ethyl diazoacetate catalyzed by ncps - ru . to a solution of ncps - ru ( 1 . 0 mol %) and alkene ( 2 mmol ) in toluene ( 2 ml ) was added dropwise a solution of allyl diazoacetate ( 1 . 0 mmol ) in toluene ( 2 ml ) over 10 h at 70 ° c . after the addition , stirring was continued until all the diazo compounds had been consumed . upon addition of hexane ( 2 ml ) the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain a pure product , the supernatant was separated and evaporated to dryness by rotary evaporation , and the residue was loaded onto a silica gel for column chromatography . in turning our attention to intermolecular carbenoid transfer reactions , we examined intermolecular cyclopropanation , n — h insertion and c — h insertion using ncps - ru as catalyst . the supported catalyst ncps - ru is active toward intermolecular cyclopropanation of alkenes , as revealed by the results depicted in table 7 . the invention further relates to intermolecular n — h insertion of amine with ethyl diazoacetate catalyzed by ncps - ru . ethyl diazoacetate ( 1 . 0 mmol ) was added in one portion to a mixture of amine ( 1 . 1 mmol ) and ncps - ru ( 1 . 0 mol %) in toluene ( 2 ml ) at 70 ° c . after the addition , stirring was continued until all of the diazo compounds had been consumed . upon addition of hexane ( 2 ml ) the reaction mixture was centrifuged , and aliquots were taken from the supernatant liquid for product identification and quantitation by 1 h nmr spectroscopy . to obtain a pure product , the supernatant was separated and evaporated to dryness by rotary evaporation , and the residue was loaded onto a silica gel for column chromatography . the carbenoid insertion into n — h bonds is an attractive carbenoid transformation for the synthesis of α - amino carboxylic compounds . [ 16 ] in this work , we found that the ncps - ru catalyzed intermolecular n — h insertion reactions could be performed without using a slow addition procedure or an inert atmosphere . the n — h insertion products were obtained in high yields by one pot reaction of amine and ethyl diazoacetate in toluene at 70 ° c . in open atmosphere ( i . e . without ar / n 2 protection ). complete substrate conversion was observed within 1 h ( table 8 ). no diazo compound coupling product was formed . in the literature , most reported metal - catalyzed intermolecular n — h insertion reactions using diazo compounds were conducted in a millimole scale . [ 16 ] in this work , we have examined the feasibility of scaling up the intermolecular n — h insertion reaction of aniline and ethyl diazoacetate using 0 . 1 mole of substrate . ( table 8 , entry 8 ). ethyl diazoacetate ( 0 . 10 mol ) was added in one portion to a mixture of aniline ( 0 . 11 mol ) and ncps - ru ( 0 . 1 mol %) in toluene at 70 ° c . in open atmosphere . complete substrate conversion was formed within 1 h . n - phenylglycine ethyl ester was obtained in 97 % yield . at a lower catalyst loading ( 0 . 01 mol %) intermolecular n — h insertion in a 0 . 1 mole scale took a longer reaction time ( 4 days ) for complete consumption of ethyl diazoacetate , no diazo coupling products ( fumarte / maleate ) were detected by 1 h nmr analysis of the reaction mixture . n - phenylglycine ethyl ester was obtained in 93 % yield . a ) m . p . doyle , m . a . mckervey , t . ye , modern catalytic methods for organic synthesis with diazo compounds , wiley , new york , 1998 ; b ) m . p . doyle , d . c . forbes , chem . rev . 1998 , 98 , 911 - 936 ; c ) h . m . l . davies , r . e . j . beckwith , chem , rev . 2003 , 103 , 2861 - 2904 ; d ) v . f . ferreira , curr . org . chem . 2007 , 11 , 177 - 193 ; e ) h . m . l . davies , s . j . hedley , chem . soc . rev . 2007 , 36 , 1109 - 1119 . a ) p . m . p . gois , c . a . m . afonso , eur . j . org . chem . 2004 , 3773 - 3788 ; b ) h . m . l . davies , angew . chem . 2006 , 118 , 6574 - 6577 ; angew . chem . int . ed . 2006 , 45 , 6422 - 6425 ; c ) a . g . h . wee , curr . org . synth . 2006 , 3 , 499 - 555 ; d ) h . m . l . davies , j . r . manning , nature 2008 , 451 , 417 - 424 . 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