N-[2-(Cyclohexylamino)-2-oxoethyl]-N-(4-octyloxy) phenyl-prop-2-enamide

molbank Sho No e N-[2-(Cyclohexylamino)-2-oxoe hyl]-N-(4-oc yloxy) phenyl-p op-2-enamide Shimoga D. Ganesh, Nabani a Saha *, Pa el Kucha czyk and Pe Sáha Cen e o Polyme Sys ems, Uni e si y Ins i u e, Tomas Ba a Uni e si y in Zlin, Tˇ . T. Ba i 5678, 760 01 Zlin, Czech Republic; [email p o ec ed] (S.D.G.); [email p o ec ed] (P.K.); [email p o ec ed] (P.S.) *Co espondence: [email p o ec ed]; Tel.: +420-576-038-156 Academic Edi o : No be Haide Recei ed: 1 No embe 2016; Accep ed: 8 Decembe 2016; Published: 13 Decembe 2016 Abs ac : N-[2-(Cyclohexylamino)-2-oxoe hyl]-N-(4-oc yloxy)phenyl-p op-2-enamide was p epa ed in good yield by coupling o 4(oc yloxy)aniline, Cyclohexyl isocyanide, pa a o maldehyde and ac ylic acid by mul icomponen Ugi eac ion, a oom empe a u e. The s uc u e o he newly syn hesized ipep oid de i a i e was well cha ac e ized using elemen al analysis, FTIR, NMR and mass spec al da a. Keywo ds: FTIR; NMR; pep ides; pep oids; Ugi eac ion 1. In oduc ion The ield o pep idomime ics has seen an exci ing de elopmen o e he pas se e al yea s, pa ly due o he conside able biological impo ance and pu a i e p o eoly ic s abili y o syn he ic pep oids o e na i e pep ides [ 1 – 3 ]. Recen ly, Ugi coupling [ 4 – 8 ] o a ious ca boxylic acids, amines, isocyana es and aldehydes o a se ies o ipep oids has been ound o gi e excellen yields and hese ha e also been epo ed o exhibi an i ungal and an imic obial ac i i ies [ 9 – 13 ]. In addi ion o such applica ions, ipep oids also ind applica ion as low molecula weigh gela o s (LMWGs) [ 14 , 15 ]. The sel -assembling na u e o low molecula weigh o ganic compounds o o m physical gels by non-co alen in e ac ions such as hyd ogen bonding, an de Waals in e ac ions, π – π s acking, e c. [ 16 ] can be a ibu ed o he p esence o lexible sol ophilic alipha ic g oups and igid sol ophobic unc ional g oups. Also, p e ious explo a ion o cyclohexyl moie y in he ipep oids gene ally shows e ec i e gela ion p ope ies [ 17 ]. Qui e ecen ly, Biswas e al. epo ed a new class o pep oid-based low molecula weigh o ganogela o s by he aza-Michael addi ion eac ion be ween glycinamide and subs i u ed alkyl ac yla es [ 18 ]. In his s udy, we epo he p epa a ion o new ipep oid wi h unc ional ac yl and cyclohexyl moie y. The syn hesis o he i le compound was achie ed by one-po Ugi mul i-componen eac ion om less expensi e aw ma e ials. The syn he ic alue o he esul ing compound can be di e ged as a p ecu so o aza-Michael addi ion eac ion o design a ie ies o pep oid-based LMWGs. The s uc u e o he i le compound was con i med by 1H, 13C-NMR, FTIR, and mass spec al da a. 2. Resul s and Discussion N-[2-(Cyclohexylamino)-2-oxoe hyl]-N-(4-oc yloxy)phenyl-p op-2-enamide was syn hesized om Ugi ou -componen (4C) eac ion in ol ing 4(oc yloxy)anile, pa a o maldehyde, ac ylic acid and cyclohexyl isocyanide a ambien condi ions o 20 h, as shown in Scheme 1. The physical appea ance o he compound is o whi e solid, insoluble in wa e , non-pola sol en s like n-hexane, and comple ely soluble in dichlo ome hane, chlo o o m, me hanol, e hanol and dime hyl sul oxide. Molbank 2016,2016, M921; doi:10.3390/M921 www.mdpi.com/jou nal/molbank Molbank 2016,2016, M921 2 o 5 Molbank2016,2016,M9212o 5  Scheme1.Syn hesiso N‐[2‐(cyclohexylamino)‐2‐oxoe hyl]‐N‐(4‐oc yloxy)phenyl‐p op‐2‐enamide. The1Hand13C‐NMRspec umda ao  he i lecompoundisingoodag eemen wi h he p oposeds uc u e.The1H‐NMRspec umo  hecompoundisdepic edinFigu e1.Thesignals co esponding oalipha ic,a oma icandamide unc ionalg oupsa eassigned o hei posi ions. Thespec umshowsmul iple signalsa δ0.88,1.18,1.31,and1.87ppmdue oalipha icp o onso  oc ylg oup.Thep o onso cyclohexylg oupwas esona eda 3.76andin he egiono 1.28–1.77 ppm.Theac yl unc ionalp o onsa e esona eda δ6.09and5.56ppm.  Figu e1.1H‐NMRspec ao desi edcompound(700MHz,CDCl3)a  oom empe a u e. Scheme 1. Syn hesis o N-[2-(cyclohexylamino)-2-oxoe hyl]-N-(4-oc yloxy)phenyl-p op-2-enamide. The 1 H and 13 C-NMR spec um da a o he i le compound is in good ag eemen wi h he p oposed s uc u e. The 1 H-NMR spec um o he compound is depic ed in Figu e 1. The signals co esponding o alipha ic, a oma ic and amide unc ional g oups a e assigned o hei posi ions. The spec um shows mul iple signals a δ 0.88, 1.18, 1.31, and 1.87 ppm due o alipha ic p o ons o oc yl g oup. The p o ons o cyclohexyl g oup was esona ed a 3.76 and in he egion o 1.28–1.77 ppm. The ac yl unc ional p o ons a e esona ed a δ6.09 and 5.56 ppm. Molbank2016,2016,M9212o 5  Scheme1.Syn hesiso N‐[2‐(cyclohexylamino)‐2‐oxoe hyl]‐N‐(4‐oc yloxy)phenyl‐p op‐2‐enamide. The1Hand13C‐NMRspec umda ao  he i lecompoundisingoodag eemen wi h he p oposeds uc u e.The1H‐NMRspec umo  hecompoundisdepic edinFigu e1.Thesignals co esponding oalipha ic,a oma icandamide unc ionalg oupsa eassigned o hei posi ions. Thespec umshowsmul iple signalsa δ0.88,1.18,1.31,and1.87ppmdue oalipha icp o onso  oc ylg oup.Thep o onso cyclohexylg oupwas esona eda 3.76andin he egiono 1.28–1.77 ppm.Theac yl unc ionalp o onsa e esona eda δ6.09and5.56ppm.  Figu e1.1H‐NMRspec ao desi edcompound(700MHz,CDCl3)a  oom empe a u e. Figu e 1. 1H-NMR spec a o desi ed compound (700 MHz, CDCl3) a oom empe a u e. 13 C-NMR spec um o he compound wi h assigned numbe ing is displayed in Figu e 2. Se e al se o signals a e ci ed in he spec um. The wo ca bonyl ca bons 3 and 5 we e ci ed a 158.8 and 167.8 ppm espec i ely. The ca bon-15 o he benzene a ached o he oxygen esona es a 166.7 ppm. The ca bon-5 is mo e deshielded o compa e wi h he ca bon-5, as he ca bon-5 is a ached di ec ly o oxygen and ni ogen, whe e he combined e ec o hese elec onega i e a oms down ield he 13 C signal and his e ec is diminished in ca bon-3. Whe ein, he ni ogen is in ol ed in esonance. The ca bon 1 and 2 o he ac yl moie y esona es a 127.9 and 128.5 espec i ely. Molbank 2016,2016, M921 3 o 5 Molbank2016,2016,M9213o 5  Figu e2.13C‐NMRspec ao desi edcompound(176MHz,CDCl3)a  oom empe a u e. 13C‐NMRspec umo  hecompoundwi hassignednumbe ingisdisplayedinFigu e2.Se e al se o signalsa eci edin hespec um.The woca bonylca bons3and5we eci eda 158.8and 167.8ppm espec i ely.Theca bon‐15o  hebenzenea ached o heoxygen esona esa 166.7ppm. Theca bon‐5ismo edeshielded ocompa ewi h heca bon‐5,as heca bon‐5isa acheddi ec ly o oxygenandni ogen,whe e hecombinede ec o  heseelec onega i ea omsdown ield he13C signaland hise ec isdiminishedinca bon‐3.Whe ein, heni ogenisin ol edin esonance.The ca bon1and2o  heac ylmoie y esona esa 127.9and128.5 espec i ely. 3.Expe imen alSec ion 3.1.Ma e ials 4(oc yloxy)aniline,cyclohexylisocyanide,pa a o maldehyde,ac ylicacid,n‐hexaneand me hanolwe ep ocu ed omSigmaAld ich(P ague,CzechRepublic).All heo he labo a o y chemicalsandsol en swe eo analy ical eagen (AR)g adeandusedwi hou  u he pu i ica ion. Doubledis illedwa e wasused h oughou  hes udy. 3.2.Ins umen a ion The1H&13C‐NMRspec awe e eco dedona700MHzB uke A anceIIIHDspec ome e  (wi ha5mmdualb oad‐bandp obe,5mmdualin e seb oad‐bandp obe,1.7mm iple esonance (1H–13C)p obe(B uke ,Leide do p,TheNe he lands) o mul inuclea applica ionsinliquidsand solidsusing e ame hylsilane(TMS)asanin e nals anda d.LCMSmeasu emen waspe o med onLiquidch oma og aphysys emwi hmassspec ome yde ec ion(Q‐TOF)—Agilen  ACCURATEMASS6530QTOFLC/MS(Agilen Technologies,San aCla a,TheUni edS a es).The elemen alanalysiswasca iedonaVARIOELIIIElemen alanalyze (Elemen a Analysensys eme GmbH,Hanau,Ge many)and he esul s o C,H,andNwe ewi hin0.4%o  he heo e ical alues. FTIRanalysiswasca iedou onNicole 6700(ATR,The moScien i ic,Wal ham,TheUni edS a es) in hescanning ange4000–600cm−1.The esolu ionwas4cm−1wi h64scansand hemeasu emen  wasdonewi hGe maniumc ys al. 3.3.Syn hesiso N‐[2‐(Cyclohexylamino)‐2‐oxoe hyl]‐N‐(4‐oc yloxy)phenyl‐p op‐2‐enamide Figu e 2. 13C-NMR spec a o desi ed compound (176 MHz, CDCl3) a oom empe a u e. 3. Expe imen al Sec ion 3.1. Ma e ials 4(oc yloxy)aniline, cyclohexyl isocyanide, pa a o maldehyde, ac ylic acid, n-hexane and me hanol we e p ocu ed om Sigma Ald ich (P ague, Czech Republic). All he o he labo a o y chemicals and sol en s we e o analy ical eagen (AR) g ade and used wi hou u he pu i ica ion. Double dis illed wa e was used h oughou he s udy. 3.2. Ins umen a ion The 1 H & 13 C-NMR spec a we e eco ded on a 700 MHz B uke A ance III HD spec ome e (wi h a 5 mm dual b oad-band p obe, 5 mm dual in e se b oad-band p obe, 1.7 mm iple esonance ( 1 H– 13 C) p obe (B uke , Leide do p, The Ne he lands) o mul inuclea applica ions in liquids and solids using e ame hylsilane (TMS) as an in e nal s anda d. LCMS measu emen was pe o med on Liquid ch oma og aphy sys em wi h mass spec ome y de ec ion (Q-TOF)—Agilen ACCURATE MASS 6530 Q TOF LC/MS (Agilen Technologies, San a Cla a, CA, USA). The elemen al analysis was ca ied on a VARIO EL III Elemen al analyze (Elemen a Analysensys eme GmbH, Hanau, Ge many) and he esul s o C, H, and N we e wi hin 0.4% o he heo e ical alues. FTIR analysis was ca ied ou on Nicole 6700 (ATR, The mo Scien i ic, Wal ham, MA, USA) in he scanning ange 4000–600 cm −1 . The esolu ion was 4 cm−1wi h 64 scans and he measu emen was done wi h Ge manium c ys al. 3.3. Syn hesis o N-[2-(Cyclohexylamino)-2-oxoe hyl]-N-(4-oc yloxy)phenyl-p op-2-enamide Pa a o maldehyde (0.042 g, 1.38 mmol) was placed in a 50 mL o ound bo omed lask, and hen added solu ion o 4(oc yloxy)aniline (0.305 g, 1.38 mmol in me hanol (10 mL). The mix u e was s i ed a oom empe a u e o 2 h. La e , ac ylic acid (0.1 g, 1.38 mmol) was added ollowed by cyclohexyl isocyanide (0.152 g, 1.38 mmol). The comple ion o he eac ion was moni o ed using Thin-laye ch oma og aphy (TLC) analysis (pe o med wi h Me ck Kieselgel 60 F 254 pla es, Me ck Millipo e, Bangalo e, India). The o ma ion o p oduc was con i med a 0.36 R (1:1 E OAc:n-hexane) a e 20 h. The eac ion mix u e was dilu ed wi h 20 mL e hyl ace a e (E OAc), washed wi h wa e (15 mL × 4), Molbank 2016,2016, M921 4 o 5 ollowed by sa u a ed solu ion o b ine (20 mL). The collec ed o ganic laye was d ied o e anhyd ous sodium sul a e and sol en was emo ed unde educed p essu e o collec he c ude p oduc (0.571 g). The c ude p oduc was i u a ed epea edly using n-hexane o ob ain he i le compound in pu e o m as an o whi e solid (0.48 g) in 84% o yield. O Whi e Solid; m.p. 199–201 ◦ C; 1 H-NMR (700 MHz, CDCl 3 ): δ 0.88 ( , 3H, J= 7.0 Hz), 1.17–1.20 (m, 8H), 1.27–1.36 (m, 4H), 1.42–1.47 (m, 4H), 1.57–1.69 (m, 4H), 1.75–1.89 (m, 2H), 3.76 (m, 1H), 3.94 ( , 3H, J= 7.0 Hz), 4.29 (s, 2H), 5.57 (d, 1H, J= 14.0 Hz), 6.07–6.11 (m, 1H), 6.37–6.44 (m, 1H), 6.87–6.88 (d, 2H, J= 7.0 Hz), 7.11–7.12 (d, 2H, J= 7.0 Hz), 13 C-NMR (176 MHz, CDCl 3 ): (ppm) 167.8, 166.7, 158.8, 134.4, 128.5, 127.9, 120.9, 115.2, 68.3, 54.7, 48.1, 32.9, 31.8, 29.2, 26.0, 25.5, 24.7, 22.6 and 14.1. Anal. calcd. o C 25 H 38 N 2 O 3 (414.580): C, 72.43; H, 9.24; N, 6.76. Found: C, 72.77; H, 9.56; N, 7.04. LCMS (ESI): m/z = 415.297 (Found), 415.2961 (Expec ed o [M + H] + ). FTIR (Ge C ys al): 3282, 3083, 2936 cm −1 (-NH S e ch), 2867 cm −1 (C-H S e ch o cyclohexane ing); 1647, 1708 cm −1 (C=O); 1120 cm −1 (C-O-C); 1422 cm −1 (C-H scisso ing); 1370 cm −1 (C-H me hyl ock); 722 cm −1 (Long chain me hyl ock). Supplemen a y Ma e ials: LCMS and FTIR spec a o he i le compound a e a ailable online a www.mdpi. com/1422-8599/2016/4/M921. Acknowledgmen s: The wo k was p incipally suppo ed by MŠMT ˇ CR-USA Kon ak II (LH14050) and he O ice o Science, O ice o Basic Ene gy Sciences, o he U.S. Depa men o Ene gy unde Con ac No. DE-AC02-05CH11231. This esea ch was also pa ially suppo ed by he Minis y o Educa ion, You h and Spo s o he Czech Republic - NPU P og am I (LO1504). Au ho Con ibu ions: S.D.G., designed he syn hesis, ca you he expe imen s o he i le compound syn hesis and w o e he a icle. N.S. and P.S., con i med he da a analysis. P.K., done he LCMS measu emen . All o he au ho s ha e ead and app o ed he inal manusc ip . Con lic s o In e es : The au ho s decla e no con lic o in e es . Re e ences 1. Simon, R.J.; Kania, R.S.; Zucke mann, R.N.; Huebne , V.D.; Jewell, D.A.; Ban ille, S.; Ng, S.; Wang, L.; Rosenbe g, S.; Ma lowe, C.K.; e al. Pep oids: A modula app oach o d ug disco e y. P oc. Na l. 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