Bhosale, D K

Gadre, LA

Jain, J J

Kusurkar, R S

Wadde, H M

NOPR

Indian Journal of ChemistryVol. 37B, December I998; pp. 1239-12451,3-Dipolar reactions for the synthesis of new substitutedisoxazolidines and isoxazolesR S Kusurkar*, D K Bhosale, LA Gadre, J J Jain & H M Wad deDepartment of Chemistry, University of Pune, Pune 411 007, IndiaReceived 9 December 1997; accepted (revised) 25 September 1998Unsaturated oximes are treated with dipolarophiles like acrylonitrile and methyl acrylate to furnish new 3,4-disubstituted and 3,5-disubstituted isoxazolidines. Reactions of unsaturated oximes with dimethyl acetylene-dicarboxylate yield 3,4-disubstituted isoxazoles.Isoxazolidines and isoxazoles are importantintermediates in multistep synthesis of complexnatural products'. Similarly isoxazoles arepharmacologically important and their derivativesexhibit antibacterial and antiviral activities2. Thering system in isoxazolidine and isoxazole isunique amongst the heterocyclic rings in the sensethat though it is stable towards variety of reagents,it can be ring opened by N-O bond cleavagereactions. Moreover there are numerouspossibilities of recyclizations arising from nitrogennucleophilicity and from a suitable substituent atC-4 or C-5 of isoxazolidine ring, forming a newheterocyclic system.In continuation with our studies3 incycloaddition reactions, we investigated reactionsof unsaturated aldoximes as well as ketoximes withconventional olefinic and acetylenic dipolaro-philes.The results obtained in these reactions arepresented in this paper.1,3-Dipolar reactions using unsaturatedoximes 1-16 (Scheme I) with olefinic dipolaro-philes. We have reported} earlier the reactions offurfuraldoxime and thiophene-2-aldoxime withconventional dipolarophiles which afforded 1,3-dipolar cycloadducts. To investigate the change inthe reaction course by introducing a substituent, 5-nitrofurfuraldoxime 1 was treated with acrylo-nitrile at 120°C in a sealed tube. The productshowed presence of cyano group and absence ofhydroxyl group which indicated it to be formed bycycloaddition along with Michael addition.Chromatographic separation gave a isomericmixture which when rechromatographed furnishedA~N-OH, XA'~0X~N-OH3 X =0. A, = H4 X =0. A, = Sr5 X = N'CH3, A, = H~A'~N-OH ~CH=CH-CH=N-OHA:!A.,.lN) VH 9~A'~N-OHA:!A)11 A, = ~ = H, A:! = OCH312 A, = A:!= OCH3. ~ = H13 A,-A:! = Methylenedioxy, ~ = H14 A, = H, A:! = N02, ~ = CH315 A, = H, A:! = OCH3, ~ = CH31 X = O. A, = N022 X = NH, A, = H6 A,=A:!=~=H7 A, = A:!= H, ~ = CH38 A, = A:!= OCH3, ~ = HQCH:N-OHCI10Scheme I-Unsaturated oximes used for 1,3-dipolar reactionstwo oily compounds. Amongst the expected fourisomers, the above two were identified using 'nNMR spectral data. One of the isomers showed atriplet at 8 4.9 and the other showed a dd at 8 5.0for one proton. Both the isomers were shown to be5-cyano isomers and the above signals wereassigned to C5-H which was expected 'to be themost downfield alicyclic signal amongst all theisomers. However due to the cis relationship, ofC3-H with cyano group, trans isomer 16a showed adownfield triplet (at 8 4.47) of CrH. In the cisisomer 16b C3-H was resonating as a triplet at 84.0. In both the spectra low intensity signals of1240 INDIAN 1. CHEM, SEC B, DECEMBER 1998minor amount of 4-cyano isomers were also seen.Reaction with methyl acrylate furnished a isomericmixture of cycloadduct 17, from which 4-cyanoisomers 17c & d were isolated (Scheme II,Table I).By changing the heteroatom, reactions werecarried out using pyrrole-2-aldoxime 2 withacrylonitrile and methyl acrylate. These reactionsfurnished mixtures of isomers of 1,3-dipolarcycloadducts from which 4- substituted isomerswere separated and identified as 18d and 19c & dusing 1H NMR spectral data.Cyc1oaddition reactions using benzofuran-2-aldoxime 3 with acrylonitrile furnished all four(R1R-C=N-OHI _...!!-- ...••••.H+16a R=2-(5-nitrofuryl),R3=H,RI=a CN 17e R=2-(5-nitrofuryl)R3=H,RI=aCOOCH316b R=2-(5-nitrofuryl),R3=H,R1=PCN 17d R=2-(5-nitrofuryl)R3=H,RI=pCOOCH320a R=2-benzofuryl, R3=H,R1= aCN 18e R=2-(pyrrolyl),R3=H, R1=<xCN,20b R=2-benzofuyl,R3=H,RI=pCN 18d R=2-(pyrrolyl),R3=H, R1=PCN22a R=2(bromobenzofuryJ),R3=H,R1=aCN 1ge R=2-(pyrrolyl),R3=H ,R1=<xCOOCH322b R=2-(5-bromobenzofuryl), 19d R=2-(pyrrolyl), R3=H ,R3=H,R1=PCN R,=PCOOCH330a Restyryl, R3=H, R,=aCN 20e R=2-benzofuryl ,R3=H,R,=cx:CN30b R=styryJ, R3=H, R,=PCN 20d R=2-benzofuryl, R3=H,R,=PCN31a Restyryl, R3=H , R,= aCOOCH3 21e R=2-benzofuryl, R3=H,R,=cx:COOCH331b R=styryl,R3=H, R,=PCOOCH3 21d R=2-benzofuryl, R3=H,R,=PCOOCH332a R=2-chJoro-l-cyc1ohexyl, R3=H,R,=aCN 23e R=2-(5-bromobenzofuryl) , R3=H,R,=aCOOCH332b R=2-chloro-l-cyc1ohexyl,R3=H, R,=PCN 23d R=2-(5-bromobenzofuryl),R3=H,R,=PCOOCH336a R=p-nitrophenyl, R3=CH3.R, = aCN 30c Restyryl ,R3=H, R1=aCOOCH336b R=p-nitrophenyl,R3=CH3.R,=PCN 30d Restyryl. R3=H, R1=PCOOCH337a Rep-merhoxyphenyl.Rjef'H; 31e Restyryl, R3=H,RI =aCN R1=aCOOCH337b Rep-methoxypherryl.Rj=Cl-lj 31d Restyryl, R3=H,R,= pCN R1=PCOOCH338a R=3,4-dimethoxyphenyl,R3=H, 33e R=2-chloro-l-cyc1ohexyl,R 3=H, R, =aCOOCH3R1=aCN38b R=3,4-dimethoxyphenyl, R3=H, R,=PCN 33d R=2-chloro-l-cyc1ohexyl,R3=H, R I=PCOOCH339a R=3,4-Methylenedioxy,R3=H, R1=aCN 36e Rep-nitrophenyl.Rj-Cl+;R1=aCN39b R=3,4-Methylenedioxy,R3=H, ~,=PCN 36d Rep-nitrophenyl.Rjef.HjR,=PCN37e R=p-methoxyphenyl,R3=CH3.R,=aCN37d Rep-methoxyphenyl.Rjef.HjR I=PCN38e R=3,4-dimethoxyphenyl,R3=H, R1= aCN38d R=3,4-dimethoxyphenyl,R3=H, R1= pCN3ge R=3,4-Methylenedioxy,R3=H,R1=aCN39d R=3,4-Methylenedioxy, R3=H, R1= pCNScheme II-l,3-Dipolar reactions using olefinic dipolarophiles.C mpd16a16bKUSURKAR et al.: SYNTHESIS OF ISOXAZOLIDINES & ISOXAZOLES 1241haracterisation data of individual stereo and regio isomers of isoxazolidines 16-39 and isoxazoIes 40-4217 Thickoil18d 115+216d Thick oil202020Thick oil78-9Yield(%)45'H NMR (CDCI3. 0, ppm)2.55-2.75 (m, 3H, CH2CN, C4-H), 2.8-3.3 (m, 3H, NCH2, C4-H), 4.47 (t,J=6.2Hz, IH, CrH), 4.9 (t, J=7.5Hz, IH, Cs-H), 6.65 (d, J=3.7Hz, IH, C3-Hoffuran ring), 7.32 (d, J=3.7Hz, I H, C4-H of furan ring).45 2.46-3.75 (2m, 6H, NCH2CH2, C4H2), 4.0 (t, J=7.5Hz, I H, CrH), 5.0 (dd,J=3.7, 8.7Hz, IH, Cs-H), 6.7 (d, J=3.7Hz, I H, CrH of furan ring, 7.35 (d,J=3.7Hz, IH, C4-H offuran ring).110-3108-1040 2.45-2.8,2.8-3.3 (2m, 5H, NCH2CH2, C4-H), 3.57-3.8 (2s, 6H, 2COOMe),4.0-4.8 (m, 3H, CSH2' C3-H), 6.6 (m, IH, CrH of furan ring), 7.3 (bs, I H, C4-H of furan ring).20 2.4-2.67 (m, 2H, CH2CN), 2.67-3.12 (m, 2H, NCH2), 3.45-3.78 (m, IH, C4-H),3.9-4.48 (m, 3H, CrH, CSH2), 6.2-6.4 (m, 2H, C)H, C4-H of furan ring),6.9-7.0 (m, I H, Cs-H of furan ring), 8.6-9.0 (bs, I H, NH).20 2.5-2.7,2.8-3.1 (2m, 4H, NCH2CH2), 3.6-3.7 (2S, 6H, 2COOMe), 3.3-3.8 (m,2H C4-H, C3-H), 3.9-4.2 (m, 2H CSH2), 6.0-6.2 (m, I H, C4-H of furan ring),6.6- 6.8 (m, 2H, Cs-H, C3-H of furan ring), 8.0-8.3 (bs, I H, NH).30 2.54-2.77 (t.J=6.3Hz, 2H, CH2CN), 2.9-3.3 (m, 4H, C4H2, NCH2), 4.4 (t,J=7.5Hz, IH, CrH), 4.95 (t, J=6.3 Hz, I H, Cs-H), 7.7 (s, IH, CrH of furanring), 7.7-7.8 (m, 4H, benzofuryl protons).40 2.5-2.77 (t, J=7.5 Hz, 2H, CH2CN), 2.9-3.3 (m, 4H, C4H2, NCH2), 4.0 (t,J=7.5Hz, 1H, CrH), 4.95 (t, J=6.3Hz, IH, Cs-H), 7.7 (s, I H, C3-H of furanring), 7.2-7.8 (m, 4H, benzofuryl protons).Thick oilM+333Thick oil88-9210 2.5-2.8 (t, J=7.5 Hz, 2H, CH2CN), 2.9-3.2 (t, J=7.5 Hz, 2H, NCH2), 3.6 (m,I H, C4-H), 4.2-4.5 (m, 3H, CsH2.CrH), 6.8 (s, IH, C)-H of furan ring), 7.23-8.0 (m, 4H, benzofuryl protons).Thickoil10 2.5-2.7 (t, J=6.3 Hz, 2H, CH2CN), 2.9-3.2 (t, J=6.3 Hz, 2H, NCH2), 3.8 (m,1H, C4-H) 4.2-4.5 (m, 3H, CSH2' CrH), 6.8 (s, I H, C)-H of furan ring),7.23-7.4 (m, 4H, benzofuryl protons).20 2.5-2.8 (t, J=7.5 Hz, 2H, CH2COOMe), 3.0-3.3 (m, 3H, C4-H, NCH2) , 3.5, 3.6(2s, 6H, 2COOMe), 4.2-4.5 (m, 3H CSH2' C)-H), 6.7 (s, IH, C)-H), 7.1-7.8(m, 4H, benzofuryl protons).80 2.5-2.7 (m, 2H, CH2CN), 2.8-3.3 (m, 4H, NCH2, C4H2), 4.07 (t, J=8.7Hz, I H,CrH), 5.0 (dd, J=7.5, 3.7Hz, I H, Cs-H), 6.8 (s, IH, CrH of furan ring), 7.4 (s,IH, C4-H of furan ring), 7.7 (bs, 2H, benzofuryl protons).20 2.5-2.7 «, J=6.3Hz, 2H CH2COOMe), 3.0-3.4 (m, 3H, C4-H, NCH2), 3.6-3.7(2s, 6H, 2COOMe), 4.2-4.4 (m, 3H, C)-H, CSH2), 6.7 (s, IH, CrH), 7.1-7, 7(m, 3H, benzofuryl protons).2.59-2.82,2.91-3.22,3.27-3.66 (3m, alicyclic & aliphatic protons), 3.74, 3.93,4.0 (3s, 3H, NCH3), 4.0-4.8, 4.9-5.2 (2m, alicyclic protons), 6.61, 6.65, 6.72,6.82 (4s, IH, CrH of indole ring), 7.28-7.7 (m, 3H, aromatic protons), 7.74(d, J=7.5Hz, 1H, aromatic protons).1.08-1.41 (2t, J=7.7Hz, 2COOCH2CH3), 3.86-4.2 (2q, J=7.7Hz,2COOCH2CH3), 2.5-2.75, 2.76-3.08 (2m, alicyclic protons), 3.61-3.86 (s,NCH3), 4.25-4.8 (m, Cs-H), 6.41, 6.5 (2s, CrH of indole ring), 6.91-7.16 (m,aromatic protons), 7.5 (d, J=7.5Hz, aromatic protons).6072Contd-I ,1242 INDIAN J. CHEM, SEC B, DECEMBER 19981.92-2.22,2.28-3.16,3.16-3.48, (3m, 14H, aliphatic & alicyclic pr tons),3.8(s, 6H, 2COOMe), 4.04-4.82 (m, 2H, alicyclic protons).Compd26mixture ofisomers27mixture ofisomers28mixture ofisomers29mixtureof isomers30a+b*30c/d*31a1b*31c/d*Thick oilYield(%)62Table 1- Characterisation data of individual stereo and regio isomers of isoxazolidines 16-39 and isoxazoles 40-42- ntdThick oil 75175-8Thick oilThick oil76Thick oilThick oil32a+bt Thick oil33c/d Thick oil 6734 Thick oil 52mixture ofisomers35mixture ofisomersThick oil138-9lH NMR (CDCh. 0, ppm)2.5-2.77,2.88-3.25 (2m, 4H, NCH2CH2CN, C4-H), 3.41-3. 5,6.831-4.55,49(2m, dd, J=7.7, 4.1Hz, together 4H, C5-H, CrH, NCH2- CH C ),7.05-75 (m,aromatic protons, C2-H), 7.55-8.0 (m, C4-H of indole ring), ~.2;7 (bs, NH .2.38-2.8, 2.86-3.3 (2m, alicyclic & aliphatic protons), 3.52, ij.6B, 3.77 (3 ,2COOMe), 4.08-4.41, 4.55-4.86 (2m alicyclic protons, C5-I- ), 6.88-7.47 ,C2H of indole ring, aromatic protons), 7.5-7.86 (m, C4-H 0 indole ring), ~ 19(bs, 1H, NH).2.41-2.75,2.75-3.25 (2m, alicyclic &aliphatic protons), 3.88 3.}n, 3.94 ( s20Me), 4.0-4.47 (m, alicyclic protons), 4.9 (bt, J=7.7Hz, C5 H), 6.75, 7.3 2s,CTH, C4-H of indole ring), 6.97-7.27 (rn, C2-H of indole ring), 8.0 (bs, N ~'. \ I.2.44-2.77,2.77-3.19 (2m, alicyclic and aliphatic protons), 3.~-4 0 (bs, 20 rland 2COOMe), 4.16-4.36 (m, alicyclic protons), 4,5-4.8 (m, C5-J-n, 6.72 ( ,CTH of indole ring) 6.92-7.0 (m, CrH and C4-H of indole ri~g) 7.88 (bs,NH). \2.4-2.88, 2.88-3.12, 3.12-3.64 (3m, alicyclic & aliphatic prot~ns), 4.99 (d!J=3.8, 5.14Hz, IH, C5-H), 6.28 (dd, J=7.7, 15Hz, IH, olefill1~ protons), 6.(d, J=15Hz, IH, olefinic protons), 7.4-7.84 (m, 5H, aromatic ro ons).65702.64-3.04,3.16-3.88,4.08-4.64 (3m, 8H, aliphatic & alicyclic pr tons),6.4(dd, J=7.7, 15Hz, IH, olefinic proton), 6.86 (d, J=15Hz, IH, JlefiniC proto)7.4-7.82 (m, 5H, aromatic protons).2.5-2.89, 3.0-3.42 (2m, 7H, aliphatic & alicyclic protons ), 3. . (s,3H,COOMe), 3.86 (s, 3H, COOMe), 4.78 (t, IH, C5-H), 6.24 (dd, 1="1.7, 15HzIH, olefinic proton), 6.8 (d, J=15Hz, IH, olefinic proton), 7,2 '7.84 (m, 5H,aromatic protons).2.64-3.6 (m, 6H, aliphatic & alicyclic protons), 3.84 (s, 3H, C~O~e), 3.88 s3HCOOMe), 4.04-4.40 (m, 2H, aliphatic protons), 6.36 (dd, J~7.7" 15Hz, 14,olefinic proton), 7.92 (d, J=15Hz, IH, olefinic proton), 7.4-8.0 (m 5Haromatic protons).1.53- 1.98, 2.36-2.58, 2.58-2.84, 2.84-3.50 (4m, aliphatic & alicycltc protons,4.12 (t, J=9Hz CrH), 4.52 (t, J=9Hz, CrH), 4.68-5, I0 (m, C5-1tI).1.72 (s, 3H, CH3), 1.8 (s, 3H, CH3) 2.06-2,5, 2.6-3.36, 3.54-3.8, ~.~6-4.84 (rr13H, aliphatic and alicyclic protons), 4,84-5.26 (m, IH C5-H), 7.h- .86 (m, 8indole ring protons), 8.0-8.4 (m, 2H C4-H of indole ring), 8.4-8J8 m, 2H, Nof indole ring). I2.36-2.42 (rn, CH3 & aliphatic protons), 2.42-3.08, 3.08-3.40 (2~' icyclicprotons), 3.76 (s, 4COOMe), 4.04-4.34, 4.52-4.78 (2m, alicyclic pre tons), 7.37.72,8.0-8.24 (2m, indole ring protons), 8.5-8.82 (m, NH, exchai geab\e withD20).1.7 (s, 3H, CH3), 2.68-3.30 (m, 6H, alicyclic & aliphatic protons) 4.8 (t,J=7.7IHz, IH, C5-H), 7.9 (d, J=9Hz, 2H, aromatic protons), 8.44 (d, J=9Hz,2H, aromatic protons).45ContdKUSURKAR et al.: SYNTHESIS OF ISOXAZOLIDINES & ISOXAZOLES 1243able J- Ch racterisation data of individual stereo and regio isomers of isoxazolidines 16·39 and isoxazoles 40·42-ContdIH NMR (CnCI3• 0, ppm)Compd Yield(%)m.p.(0C)122-3 1.84 (s, 3H, CH3), 2.64-3.16 (m, 4H, aliphatic protons), 3.72 (m, IH, C4-H),4.18-4.64 (m, 2H, Cs-H), 8.0 (d, J=9Hz, 2H, aromatic protons), 8.52 (d, J=9Hz,2H aromatic protons).37a&b* Thick oil 1.5 (s, 3H, CH3), 1.68 (s, 3H, CH3), 2.62-3.52 (m, 12H, aliphatic & alicyclicprotons), 3.9 (s, 6H, 20CH3), 4.08-5.08 (s, 2H, alicyclic protons), 7.0-7.24 (m,4H aromatic protons), 7.44-7.8 (m, 4H, aromatic protons).37c* 128-9 1.6 (s, 3H, CH3), 2.64-3.04.3.34-3.72 (m, 4H, & m, I H aliphatic & alicyclicprotons), 3.92 (s, 3H, OCH3), 4.12-4.60 (m, 2H, alicyclic protons), 7.16 (d,J=9Hz, 2H, aromatic protons), 7.76 (d, J=9Hz, 2H, aromatic protons).38a/b Thick oil 49 2.25-2.8,2.8-3.3 (2m, 7H, aliphatic and alicyclic protons), 3.6, 3.74 (2s, 6H,2COOMe), 3.81 (2s, 6H, 20Me), 4.36-4.83 (m, IH, Cs-H), 6.47-7.1 (m,3H,aromatic protons).38cJd 44 2.3-2.78,2.78-3.19,3.19-3.45 (3m, 7H, aliphatic and alicyclic protons), 3.51,3.52 (2s, 6H, 2COOMe), 3.85 (s, 6H, 20Me), 4.0-4.25 (m, IH, Cs-H), 6.61-7.05 (m, 3H, aromatic protons).Thick oil39a/b Thick oil 56 2.22-2.75,2.75-3.33,3.91-4.15 (3m, 7H, aliphatic and alicyclic protons), 3.53,3.72 (2s, 6H, 2COOMe), 4.17-4.69 (m, I H, Cs-H), 5.86 (s, 2H, OCH20), 6.45-6.89 (m, 3H, aromatic protons).39cJd Thick oil 18 2.25-2.67,2.67-3.0,3.0-3.42 (3m, 6H, aliphatic and alicyclic protons), 3.50-3.58 (2s, 6H, 2COOMe), 3.89-4.19 (m, 2H, CSH2), 5.83 (5, 2H, OCH20), 6.42-6.94 (m, 3H, aromatic protons).40 100-\02 62 4.05 (5, 3H, COOMe),7.27-8.1 (m, 6H, aromatic & olefinic), 8.5 (m, 2H,olefinic & Cs-H).41 66 3.79(5, 3H, COOMe), 3.90 (5, 3H, OMe), 7.0 (d, J=7.5 Hz, 2H, aromaticprotons), 8.5 (d, J=7.5 Hz, 2H, aromatic protons), 8.6 (5, IH, Cs-H).12442 3.81(5, 3H, COO~e), 6.1 (5, 2H, OCH20), 6.91(d, J = 7.7 Hz, IH, aromaticprotons), 7.81 (dd, J =7.7,1.4 Hz, IH, aromatic proton), 8.6 (d, J=1.4 Hz, IH,aromatic proton), 8.65 (5, IH, Cs-H).* I yield of 30~/cJd and 31a/b/cJd is 72% & 71 % respectivelyt t I yield of 2Wb/cJd and 36a/b/cJd is 65 & 78% respectively.*T t I yield of 7lub/cJd is 76%~I I ,is ers 20 ·d of the cycloadduct which wereis I ted an characterised. The regioisomers weredi rentiated_pn the basis of the most downfieldal pf C -H. In 20a and 20b it appeared at band i 20c and 20d two protons at C-5an ared at s f.2-4.5. Discrimination between 20aa tl 20b wa darned out on the basis of chemicalsh f of C,-H. Because of the cis relationship of C3-. I .Had cyan' group, C3,-H was expected t~1resonated nfield ( 4.4)in trans isomer as co pared tot~ t in ci~ isomer(<>4.0). ~somers 20c a~d Od .weredi f rentiate on the baSIS of the chemic [I shift of68167-170C4-H which being cis to benzofuran ring, wasexpected to be more shielded. Thus the compoundhaving signal at b 3.6 was the trans isomer 20c andthe other having signal at <>3.8 was the cis isomer20d (Scheme II, Table 1).Reaction of acrylonitrile with 5-bromobenzo-furan-2-aldoxime 4, furnished only 5-cyano isomer22b in high yield. In the reactions using methylacrylate both 3 and 4 oximes furnished mixtures ofisomers of cycloadducts (21 and 23) from which21c/d and 23c/d were separated.11244IINDIAN 1. CHEM, SEC B, DECEMBER 1998Indole 2-aldoxime 5, indole-3-aldoxime 6 and15,6-dimethoxyindole-3-aldoxime 8 also gavemixtures of isomers of the cycloadducts 24, 25, 26,27, 28, and 29 respectively with acrylonitrile aswell as ethyl acrylate or methyl acrylate whichwere not separated into individual isomers(Scheme III, Table I).Cinnamaldoxime 9 and 2-chlord!-1-cyc1ohexene-aldoxime 10 when used in these: reactions gaveinitially mixtures of isomers. III the case ofcinnamaldoxime with acrylonitrile as well asmethyl acrylate, 4- and 5-cyano isomers wereseparated and identified as 30alb, 30c/d and 31a1bI3 1c/d. In the case of oxime 10 with acrylonitrile,stereoisomeric mixture of 5-isomers was isolatedin 2:5 ratio of cis(32b):trans(32a)as shown by IHNMR. With methyl acrylate, mixture of isomers of33 was obtained from which 33dd was separatedinto pure form. Veratraldoxime 12 and piperonaloxime 13 furnished mixtures of isomers 38 and 39with methyl acrylate (Scheme II,Table 1).In the last part of this work, ketoximes 7,14, and15 when treated with dienophiles gave mixtures ofisomers of the adducts 34, 35, 36, 37.1,3-Dipolar reactions using unsaturatedoximes with acetylenic dipolarophile (DMAD).Recently we have reported' a reaction ofthiophene-2-aldoxime with" DMAD whichfurnished directly 3-substituted isoxazole-4-methylester. In connection with this work, oc,~-unsaturated oximes 9, 11 and 13 were treated withDMAD. The products obtained were 4-carbo-methoxy isoxazoles 40-42 (Scheme IV, Table II).The probable mechanism can be shown as initialcyc1oaddition with Michael addition to give 4-isoxazoline which can isomerise to 3-isoxazoline.R-C=N~H~ Rl=COOMeThe two carbomethoxyl grou scan oedifferentiated or the basis of the 1act that,COOMe is viny ogous amide while ~5-COOM ISa saturated este~. Hydrolysis and deca boxylat 0of C5-COOMe might be furnishing th!e ,roductsshown in Scheme V. The PositionJo -COOgroup was confirmed from the IH I MR spec r Idata in which most downfield prot~nl C5-H Sseen around 0 8-9. In each casJ ehydra eIproducts were obtained in around 2°1 yield.(Rl Rx1R~R--C=N--OH Ik ~ Ri---- ~O24 R=2~(~~m"hYIiOdOIYI)'R,=H,R,,,,,r2S R=2-(N-methylindolyl),R3=H,R\=CG>OEt26 R=3-indoJyJ,R3=H,R\=CN27 R=3-indoJyJ,R3=H,R\=COOCH328 R=3-(5,6-dimethoxytndoJyJ),R3=H,Rh= N29 R=3_~5'6_dimethOXYindOJYJ)'R3=H'l\=(f00CH334 R=3-tndoJyJ,R3=Me,R \=CN3S R=3-indoJyJ,R3=Me,R\=COOCH3Scheme m-I,3~D;poho '''''';00' usmg OI'fiT rOIMOPh'00 MeR-C=N-OH MeOOC-C=C-COOMeI ~HR = 01CH=CH- ~::,.. MeoA)!40 41Scheme IV - J,3 Dipolar reactions usiRlR~N-OScheme VKUSURKAR et al.: SYNTHESIS OF ISOXAZOLIDINES & ISOXAZOLESC elusion Ieactions o~ unsaturated oximes 1-10 and 12-15w t double bonded dipolarophiles furnished news l) tituted isoxazolidines while those of 9, 11 and1· ith DMAD furnished substituted isoxazoles.erime tal Secionspect a were recorded in nujol on PerkinE er-337 p ctrometer and IH NMR spectra on aJea FX 9 Q spectrometer at 90 MHz in CDChu i g TMS a internal standard. Carbon/hydrogenyses w re carried out on Hosli CIH analyser .repara io of unsaturated oximes. oc,~_aturate I ximes 1-15 were prepared usingr p,orted pr cldures.eneral p ocedure for 1,3-dipolar reactions.the u a urated oxime 1-15 was added ane ess of h~ dipolarophile (acrylonitrile, methyllate, et y] acrylate or DMAD) and a pinch ofroquin ~. After passing dry nitrogen gas, thetion xt re was heated (for 12-120 hr) in as led tube a 120°C. Excess of the dipolarophileremov d The reaction mixture was chromato-phed 0 s lica gel using pet ether-ethyl acetate0%) w i h furnished the product as a thick oilare ql'ds).The isoxazolidines obtained asi k oils ere mixtures of regio- and stereo-1245isomers. In some cases the thick oil wasrechromatographed on silica gel using pet ether-ethyl acetate to furnish single isomer. IR spectra ofall isoxazolidines obtained in the reactions withacrylonitrile showed bands in the range of 2250-2260 cm-1 for -CN and with methyl. .acrylateshowed bands in the range of 1730-1770 'cm-1 for-COOMe along with the other bands. Allisoxazoles showed bands in the range of 1747-1755 cm-1 for -COOMe. All products showedsatisfactory microanalysis within the range of C0.3%, H 0.2%.AcknowledgementWe thank Mr A P Gadgil and Mrs J.P Chaudharifor analytical and spectral data. One of us (HMW)thanks the UGC, New Delhi, for the award ofteacher fellowship under FIP.References1 Grunanger P & Funzi P V, The Chemistry of HeterocyclicCompounds, Isoxazoles, Vol 49, Part I, (John Wiley, NewYork) 1991, 391,753.2 Devi V U, Ashok K, Rao K R K M, Indian J Chern29B,1990, 898.3 Kusurkar R S, Wadia M S, Bhosale D K, Tavale S S &Puranik V G, J Chern Res (S), 1996,478 J Chern Res(M),1996, 2701

1,3-Dipolar reactions for the synthesis of new substituted isoxazolidines and isoxazoles

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1,3-Dipolar reactions for the synthesis of new substituted isoxazolidines and isoxazoles

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