多组分反应文献

1、多组分反响文献One pot, three-component synthesis of novel 3, 4-dihydrophthalazin-2(1H )- yl-4-phenyl-4H-pyransP. Praveen Kumar ?, Y. Dathu Reddy, Ch. Venkata Ramana Reddy, B. Rama Devi, P. K. DubeyDepartment of Chemistry, Jawaharlal Nehru Technological UniversityHyderabad, Kukatpally, Hyderabad (AP)500085,

2、 Indiaa r t i c l e i n f o a b s t r a c tGreen and ef ?cientone pot, three-component synthesis of novel 2-amino-6- (1,4-dioxo-3,4-dihydroph-thalazin)-2(1H )-yl-4-phenyl-4H -pyran-3,5- dicarbonitriles 6has been developed by condensing 3-(1,4-dioxo-3,4- dihydrophthalazin-(1H )-yl)-3-oxopropanenitril

3、e 3, benzaldehydes 4and active methylene compounds 5using L -proline as catalyst in EtOH at RT.o 2021Elsevier Ltd. All rights reserved.Article history:Received 25December 2021Revised 4February 2021Accepted 10February 2021Available online 20February 2021Keywords:Green chemistry Phthalic anhydride Ben

4、zaldehydesActive methylene compoundsMulti-component reactions have been proved as an important tool for thesyntheses of many multi-substituted heterocyclic ring-containing compounds. 1Synthesis of different substituted 4H -pyrans has been studied in theliterature. 2 5To the best of our kno wledge, p

5、hthalaz ine moieties containingdifferent substi-tuted 4H -pyrans have not been studied.Phthalazines are important heterocycles that are known to pos-sess multiple biological activities such as antimicrobial, anticon-vulsant, antifungal, anticancer and anti-in?ammatory.6Carling et al. reported 7thesy

6、nthesis of 3-phenyl-6-(2-pyridyl)methyl-oxy-1,2,4-triazolo3,4- a phthalazinesand analogues which were found to be a key structural elementof certain CNS activedrugs. Jain et al. reported 8the synthesis of ketoglutamine tetra peptide analogues containing a 2-oxo-pyrrolidine ring as a glutamine side c

7、hain mimic which showed improved inhibition against hepatitis A virus 3C proteinase. Grasso et al. reported 9the synthesis of 6,7- methylenedioxyphthalazin-1(2H )-ones which were found to be potent anticonvulsant. Nomoto et al. reported 10the synthesis of 6,7- dimethoxyphthalazine derivatives which

8、showed relatively potent cardiotonic activity comparable to that of amrinone. Watanabe et al. reported 11the synthesis of 4-benzylamino-1-chloro-6-substituted phthalazines which were found to be vasore-laxant activatives and a number of methods have been reported for the syn thesis of phthalaz ine d

9、erivatives. 12 18Therefore, it wascon-sidered worthwhile to synthesize phthalazine moiety containing 4H -pyrans.Corresponding author. Tel.:+1*2; fax:+1*87.E-mail address:padampraveenkugmail (P.P.Kumar). 2021.02.0200040-4039/ o 2021Elsevier Ltd. All rights reserved.Keeping these results in mind and i

10、n continuation of our earlier work on phthalic anhydride, 19,20we now wish to report green and ef?cient,one-pot,three component synthesis of novel 2-amino-6-(1,4-dioxo-3,4-dihydrophthalazin- 2(1H )-yl-4-phenyl-4H -pyran-3, 5-dicarbonitriles by condensing 3-(1,4-dioxo- 3,4-dihydrophthala-zin-(1H )-yl

11、)-3-oxopropanenitrile, benzaldehydes and active meth-ylene compounds.As illustrated in Scheme 1, treatment of phthalic anhydride (1) with ethyl cyanohydrazide 21(2) in acetic acid at RT for 1h resulted in the formation of 3-(1,4-dioxo-3,4-dihydrophthalazin-(1H )-yl)-3-oxopropanenitrile (3). The stru

12、cture of this product was assigned on the basis of its spectral data. (Fordetails, please see Experimen-tal section).An interesting observation made here was that in the 1H NMR spectrum of 3the - NH- proton appeared at d 11.1as a weak but slightly broadened peak in tegrati ng for one prot on and the

13、- CH2- prot on sig nal appeared at d 4.1as asharp singlet integrating for two protons. Both these signals disappeared from the spectrum on addition of D 2O to the solution. The exchange of-NH-protonwith deuterium is well known but the- CH2- proton exchange with deuterium in- 2182the absence of any a

14、dded base is unusual. In2178P. P. Kumar et al. /Tetrahedron Letters 55(2021)2177the prese nt case, this may be due to the fact that the CH2 prot ons forman enol with adjoining CO- leading to the formation of a six-membered chelate 3A as shown below:-Then, for the one pot, three-component reaction of

15、 3, benzaldehyde 4a and malononitrile 5a were stirred together for 1h at RT in the green solvent ethanol in the presence of the green catalyst L -proline. The corresponding novel 2-amino-6-(1,4-dioxo-3,4-dihydrophthal-azin-2(1H )-yl-4-phenyl-4H - pyran-3,5-dicarbonitrile 6a was ob-tained in excellen

16、t yields on simple workup of reaction mixtures. (Fordetails, please see Experimental section). These results are shown in Table 1, entry 1.Both the catalyst and the solvent play a vital role in determining the success of the reaction in terms of rate and yields. In the ab-sence of catalyst in any so

17、lvent, there was hardly any progress in the reaction even after stirring the reactants for 10h. Various cat-alysts were also screened for this reaction in the present work, which include L -proline, piperidine, triethylamine and pyridine (Table 1). The solvents used in the present work are EtOH, MeO

18、H and DMSO. Among all the catalysts and solvents used in the pres-ent work, L -proline and ethanol proved to be the best (Table 1, en-try 1) (Scheme 2).To ?ndout the optimum concentration of the catalyst, the one-pot reaction was carried out by varying the amount of L -proline (Table 2). However, re

19、action with 30mol %L -proline as a catalyst at RT for 1h in EtOH gave good yield (85%)(Table 2, entry 4). Fur-ther increase in amount of L -proline in mentioned reaction did not have any signi?canteffect on the product yield.After having optimized the reaction conditions, the generality of the react

20、i on was con 彳medby carry ing out the conden sati on of several others 4a-4f and 5a 5b usi ng L -proli ne as a catalyst at RT for 1 2h in EtOH 6a 6lgiving very good yields and no side product formation was detected. In all cases, the three component reaction proceeded smoothly to give the correspond

21、ing products 6a - 6l in high yields. As shown in Table 3, it was found that this method works with a wide variety of substrates. It is worthy to mention that the reaction of 3, 4&5a (malononitrile)could get higher yield and require shorter reaction time than the reaction of 3, 4and 5b (ethylcyan

22、oacetate). This can be ascribed to theTable 1Effect of solvent, catalyst &temperature on reaction of 3, 4a &5a at RT yielding 6a Entry Solvent CatalystTime (h)6a (%)1Ethanol L -Proline1852Ethanol Pyridine2.5653Ethanol Triethyl amine 2.5554Ethanol Piperidine 1.5705methanol Piperidine 2706Meth

23、anol Pyridine2.5657Methanol Triethyl amine3608Methanol L -Proline1.5759DMSO Piperidine 3.55010DMSO Pyridine44511DMSO Triethyl amine4.54012DMSOL -Proline340Table 2The effect of amount of L -proline in the preparation of 6a by 3, 4a &5ain EtOH Entry Solve nt Mol %of L -proli ne Time (h)6a (%)- 1Et

24、ha nol 122Ethanol 103703Ethanol 202754Ethanol 301856Ethanol 501857Ethanol100185Refers to yields of crude products only.Table 3Characterization data, reaction time and yields of 6obtained from 3, 4&5via one-pot synthesis Entry Starting material used Product obtained Time (h)Yield - 134a 5a 6a 185

25、234b 5a 6b 183334c 5a 6c 180434d 5a 6d 1.585534e 5a 6e 1.582634f 5a 6f 1.580734a 5b 6g 285834b 5b 6h 283934c 5b 6i 2801034d 5b 6j 2801134e 5b 6k 2831234f5b6l282Refers to yields of crude products only.C Hacidity of the active methyle ne compo un ds. The cyano fun c-ti onal group has a stronger electr

26、on-withdrawing ability than the ester group, so it is easier for malononitrile bearing two cyano groups to generate an anion than with ethyl cyanoacetate in the presence of base and hence react much faster in one-pot synthesis. The structures of these products have been established on the basis of t

27、heir spectral data. (Scheme 1) (Table 3).The synthesis of 6could also be achieved in two variable but identical end-product giving step-wise syntheses. Thus, a mixture of 3and 4was stirred at RT for 20min in the presence of 30mol %L -proline in EtOH to form 7. The reaction was monitored by TLC. The

28、structures of these products have been established ear-lier on the basis of their spectral data. (Scheme 3) (Table 4).Furthermore, the compound 7was assigned E-con?gurationon the presumptionthat bulky groups in a trans position would confer thermal stability on the molecule. This has been found to b

29、e the case by a careful examination of the Frame-work molecular models of both E and Z-con?gurationsof 7wherein it wasobserved that there were minimum number of steric interactions in the E- con?guration.Then, 7was reacted with 5in the presence of 30mol %L -proline in EtOH to form the ?nalproduct 6(

30、Scheme 3) (Table 5). Similarly, a mixture of 4and 5wasstirred at RT for 20- 30min in the presenee of 30mol %L -proline in EtOH toform 8. 22The reaction was monitored on TLC. Then, 8was reacted with 3in the preseneeP. P. Kumar et al. /Tetrahedron Letters 55(2021)2177- 21822179Table 4Charaeterization

31、data, reaetion time and yields of 7obtained from 3&4Entry 123456Starting material 4a 4b 4e 4d 4e 4fProduet 7a 7b 7e 7d 7e 7fTime (min)1*5Yield-1*02-amino-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H )-yl-4-phenyl-4H -pyran- 3,5diearbonitrile with simple work up proeedures in green methods. Experiment

32、al seetionMelting points are uneorreeted and were determined in open eapillary tubes in sulfurie aeid bath. TLC was run on siliea gelGand visualization was doneusing iodi ne or UV light. IR spectra were recorded using Perk in-Elmer1000instrument in KBr pellets. 1H NMR spectra were recorded in DMSO-d

33、 6and CD 3OD using TMS as internal standard using 400MHz spectrometer. Mass spectra were recorded on Agilent-LCMS in strume nt. Starti ng materials 1,4a 4f and 5a 5b were obtai ned fromcommercial sources and used as such.Preparation of 3A mixture of 1(10mM), 2(10mM) and acetic acid (20ml) was stirre

34、d at RT for1h. At the end of this period, a colourless solid sep-arated out from reaction mixture which was collected by ?ltrationof the mixture, washed with hexane (10ml) and dried. The crude product was recrystallized from ethanol to obtain pure 3.Compound 3:Mp:150- 152° C; IR (KBr):3293 - 35

35、18cm a 1(broad,medium, - NH-),1748cm a 1(sharp,strong,- CO- ),1682cm a 1(sharp,strong,- CO- of amidegroup), 1614cm a1(sharp,strong,-CO-of amide group); 1H NMR (DMSO-d 6,400MHz):d 4.2(s,2H, C H 2), 7.9-8.0(m,4H, Ar-H ), 11.1(s , 1H ,-NH, D 2Oexchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 36.9, 114.8, 1

36、24.8, 131.1, 136.2,164.1, 164.8, 166.1; HRMS calcd for C 11H 7N 3O 3M+H+:230.0314.Found:230.0311.Preparation of 6a -6lfrom 3, 4a - 4f&5a- 5bby one-pot synthesis A mixture of 3(10mM), 4a -4f (10mM), 5a -5b (10mM), 30mol %L -proline and EtOH (20ml) was stirred at RT for 1-2h. At the end of this pe

37、riod, a colourless solidseparated out from reaction mixture which was collected by?ltrationof themixture, washed with hexane (10ml) and dried. The crude product was recrystallized from ethanol to obtain pure 6a- 6l .Compound 6a :Mp:138-140° C; IR (KBr):3306-3401cm a1(broad,medium, - NH-),2218cm

38、 a 1(sharp,strong,- CN- ),1706cm a 1(sharp,strong, - CO- of amidegroup), 1659cm a1(sharp,strong, -CO-of amide group); 1H NMR (DMSO-d 6, 400MHz):d 6.1(s,1H,-CH ), 7.5-8.1(m,9H, Ar-H ), 9.6(s,2H,-NH 2),11.6(s,1H,-NH, D 2O exchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 48.5, 75.5,86.3, 114.6, 115.1, 124.

39、5, 127.9, 128.6, 129.7, 130.7, 134.1, 136.0, 155.8,157.4, 163.0, 163.6; HRMS calcd for C 21H 13N 5O 3M+H+:384.0427.Found:384.0424.Refers to yields of crude products only.Table 5Characterization data, reaction time and yields of 6a- 6lEntry*324Starting material used 7a 7b 7c 7d 7e 7f 7a 7b 7c 7d 7e 7

40、f 8a 8b 8c 8d 8e 8f 8g 8h 8i 8j 8k 8l5a 5a 5a 5a 5a 5a 5b 5b 5b 5b 5b 5b 1*3Product obtained 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6lYieldRefers to yields of crude products only.?nalproduct 6. (Scheme 3) (Tableof 30mol %L -proline in EtOH to form the 5).Encouraged by t

41、he above results, synthesis of 6has been achieved successfully through tandem synthesis by using step-53wise sequences e3t4! 7! 6T&e4t5! 8! 6T(Scheme 4) ConclusionIn summary, we have successfully adapted a simple one pot as well as stepwise and tandem process for the synthesis of novel21822180P.

42、 P. Kumar et al. /Tetrahedron Letters 55(2021)2177Compound 6b :Mp:180- 182° C; IR (KBr):3309- 3405cm a 1(broad,medium, - NH-),2210cm a 1(sharp,strong,- CN- ),1716cm a 1(sharp,strong, - CO- of amidegroup), 1656cm a1(sharp,strong, - CO-of amide group) 1H NMR (DMSO-d 6, 100MHz):d 2.3(s,1H,- CH 3),

43、 6.1(s,1H,-CH ), 7.5 - 8.1(m,8H, Ar-H ), 9.6(s,2H,-NH 2), 11.6(s,1H,- NH , D 2O exchangeable ); 13C NMR (DMSO-d 6, 400MHz):d 37.3, 48.1, 75.6, 86.5, 114.3, 115.1, 124.5,127.9, 128.6, 129.6, 130.7, 134.0, 136.1, 155.6, 157.2, 163.4, 163.5; M +1=398.Compound 6c :Mp:140-142° C; IR (KBr):3303-3405c

44、m a1(broad,medium, - NH-),2217cm a 1(sharp,strong,- CN- ),1704cm a 1(sharp,strong, - CO- of amidegroup), 1658cm a1(sharp,strong, - CO-of amide group); 1H NMR (DMSO-d 6, 400MHz):d 3.8(s,1H,- OCH 3), 6.3(s,1H,- CH ), 7.6- 8.4(m,8H, Ar-H ),9.4(s,2H,- NH 2), 11.5(s,1H,- NH, D 2O exchangeable ); 13C NMR

45、(DMSO-d 6, 100MHz):d 48.3, 53.9, 75.3, 85.6, 114.1, 115.3, 124.7,127.9, 128.6, 129.7, 130.6, 134.1, 136.0, 155.8, 157.0, 163.3, 163.6; M +1=414.Compound 6d :Mp:160- 162° C; IR (KBr):3304 - 3402cm a 1(broad,medium, - NH-),2211cm a 1(sharp,strong,- CN- ),1704cm a 1(sharp,strong, - CO- of amidegro

46、up), 1655cm a1(sharp,strong, - CO-of amide group); 1H NMR (DMSO-d 6, 100MHz):d 6.0(s,1H,- CH ), 7.1- 8.3(m,8H, Ar-H ), 9.7(s,2H,-NH 2) 11.0(s,1H,-NH, D 2O exchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 48.1, 75.5, 85.5,114.5, 115.0, 124.9, 127.6, 128.7, 129.7, 130.6, 134.2, 136.6, 155.4, 157.8, 163.2,

47、163.6; M +1=429. Compound 6e :Mp:180- 182° C; IR (KBr):3306- 3404cma 1(broad,medium,-NH- ),2214cm al(sharp,strong,- CN- ),1702cma 1(sharp,strong,-CO- of amide group), 1655cm a 1(sharp,strong, - CO- of amidegroup); 1H NMR (DMSO-d 6, 100MHz):d 2.2(s,1H,- CH 3), 6.2(s,1H,- CH ), 7.5-8.2(m,8H, Ar-H

48、 ), 9.7(s,2H,-NH 2), 11.6(s,1H,-NH, D 2O exchangeable ); 13C NMR (DMSO-d 6, 400MHz):d 37.3, 48.1, 75.3, 86.4, 114.5, 115.3, 124.5,127.6, 128.7, 129.7, 130.6, 134.1, 136.0, 155.8, 157.0, 163.2, 163.7; M +1=398.Compound 6f :Mp:178-180° C; IR (KBr):3302-3401cm a1(broad,medium, - NH-),2217cm a 1(sh

49、arp,strong, - CN- ),1707cm a 1(sharp,strong, - CO- of amide group), 1653cm a1(sharp,strong, - CO-of amide group); 1H NMR (DMSO-d 6, 400MHz):d 5.8(s,1H,- CH ), 7.0- 7.7(m,8H, Ar-H ), 9.1(s,2H,-NH 2),10.9(s,1H,- NH, D 2O exchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 48.5, 75.3,86.2, 114.6, 115.3, 124.5

50、, 127.6, 128.7, 129.7, 130.6, 134.1, 136.0, 155.8, 157.0, 163.2, 163.7; M +1=418. Compound 6g :Mp:206-208° C; IR (KBr):3310-3416cm a 1(broad,medium, -NH- ),2216cm a 1(sharp,strong, - CN- ),1713cm a1(sharp,strong,-CO-of amide group), 1654cm a1(sharp,strong,-CO-of amidegroup); 1H NMR (DMSO-d 6, 4

51、00MHz):d 1.2(t,3H,- CH 3), 3.9(m,2H,- CH 2),5.4(s,1H,- CH ),7.5- 7.9(m,9H, Ar-H ), 9.1(s,2H,-NH 2), 11.3(s,1H,-NH, D 2Oexchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 19.8, 49.3, 57.7, 76.3, 110.9,113.4, 115.9, 116.4, 119.9, 120.8, 125.3, 125.9, 126.9, 127.6, 128.6, 130.9, 137.0, 139.0, 140.5, 158.6, 1

52、64.1, 164.9; M +1=431.Compound 6h :Mp:175-178° C; IR (KBr):3315-3418cm a1(broad,medium, - NH-group),2214cm a 1(sharp,strong,- CN- ),1716cm a 1(sharp,strong,-CO- of amidegroup), 1655cm a1(sharp,strong, - CO-of amide group); 1H NMR (DMSO-d 6, 400MHz):d 1.2(s,3H,- CH 3), 1.3(t,3H,- CH 3), 3.8(m,2H

53、,- CH 2), 5.4(s,1H,-CH ), 7.5- 7.8(m,8H, Ar-H ), 9.1(s,2H,-NH 2), 11.2(s,1H,-NH, D 2Oexchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 19.8, 36.3, 49.3, 57.7, 77.5, 110.8, 113.4, 115.9, 116.3, 119.9, 120.8, 125.6, 126.9, 127.6, 128.3, 130.9,137.5, 139.0, 140.6, 158.9, 164.1, 164.6; M +1=445.Compound 6i :

54、Mp:170-172° C; IR (KBr):3313-3415cm a 1(broad,me dium, -NH-),2218cm a 1(sharp,strong, - CN- ),1715cm a 1(sharp,strong, - CO- of amide group), 1656cm a1(sharp,strong, - CO-of amide group); 1H NMR (DMSO-d 6, 400MHz):d 1.5(t,3H,- CH 3), 3.6(s,2H,- OCH 3), 4.1(m,2H,- CH 2), 5.8(s,1H,CH ), 7.5 8.0(m

55、,8H, Ar-H ), 9.3(s,2H, NH 2), 11.1(s,1H, NH, D 20exchangeable ); 13C NMR (DMSO-d 6, 100MHz):d 19.8, 47.3, 49.4, 57.5, 78.7,110.8, 113.0, 115.6, 116.7, 118.5, 120.9, 125.6, 126.4, 127.3, 127.4, 130.5,137.3, 139.9, 141.5, 158.9, 164.0, 164.1; M +1=461.Compound 6j :Mp:88- 90° C; IR (KBr):3312 - 34

56、18cm a 1(broad,medium, - NH-),2218cm a 1(sharp,strong,- CN- ),1718cm a 1(sharp,strong,- CO- of amidegroup), 1657cm a1(sharp,strong, - C0-of amide group); 1H NMR (DMS0-d 6, 400MHz):d 1.3(t,3H,- CH 3), 4.0(m,2H,- CH 2), 6.1(s,1H,- CH ), 7.3-8.1(m,8H, Ar-H ), 8.8(s,2H,-NH 2), 11.2(s,1H,-NH, D 2O exchan

57、geable ); 13C NMR (DMSO-d 6, 100MHz):d 19.3, 49.4, 56.7, 75.3, 110.8, 113.4, 116.9,117.4, 119.9, 120.8, 125.3, 126.9, 127.6, 128.7, 130.3, 137.0, 139.4, 141.5,158.1, 164.6, 164.9; M +1=476.Compound 6k :Mp:120-122° C; IR (KBr):3319-3419cm a1(broad,medium, - NH-),2218cm a 1(sharp,strong, - CN- ),

58、1717cm a 1(sharp,strong, - CO- of amide group), 1653cm a1(sharp,strong, - CO-of amide group); 1H NMR (DMSO-d 6, 400MHz):d 1.2(s,3H,- CH 3), 1.3(t,3H,- CH 3), 3.9(m,2H,- CH 2), 5.4(s,1H,-CH ), 7.3- 7.8(m,8H, Ar-H ), 9.0(s,2H,-NH 2), 11.2(s,1H,-NH, D 2Oexchangeable ); 13CNMR (DMSO-d 6, 100MHz):d 19.8, 37.6, 49.4, 57.4, 78.7,110.9, 113.3, 115.8, 116.9,