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.
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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.
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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.
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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 .
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