Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters

15 Pages·2017·1.07 MB·English

molecules
Article
Synthesis and Antifungal Activity of Novel
3-Caren-5-One Oxime Esters
MinHuang,Wen-GuiDuan*,Gui-ShanLin*,KunLiandQiongHu
SchoolofChemistryandChemicalEngineering,GuangxiUniversity,Nanning530004,Guangxi,China;
[email protected](M.H.);[email protected](K.L.);[email protected](Q.H.)
* Correspondence:[email protected](W.-G.D.);[email protected](G.-S.L.);
Tel.:[phone](W.-G.D.);Fax:[phone](W.-G.D.)
Received:28August2017;Accepted:8September2017;Published:12September2017
Abstract: Aseriesofnovel3-caren-5-oneoximeestersweredesignedandsynthesizedbymulti-step
reactionsinanattempttodeveloppotentantifungalagents.TwoE-Zstereoisomersoftheintermediate
3-caren-5-oneoximewereseparatedbycolumnchromatographyforthefirsttime. Thestructuresof
alltheintermediatesandtargetcompoundswereconfirmedbyUV-Vis,FTIR,NMR,ESI-MS,and
elementalanalysis. Theantifungalactivityofthetargetcompoundswaspreliminarilyevaluated
by the invitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola,
Alternaria solani, Cercospora arachidicola, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis, and
Colleterichumorbicalareat50µg/mL.Thetargetcompoundsexhibitedbestantifungalactivityagainst
P.piricola,inwhichcompounds(Z)-4r(R= β-pyridyl),(Z)-4q(R=α-thienyl),(E)-4f(cid:48) (R=p-FPh),
(Z)-4i(R=m-MePh),(Z)-4j(R=p-MePh),and(Z)-4p(R=α-furyl)hadinhibitionratesof97.1%,
87.4%,87.4%,85.0%,81.9%,and77.7%,respectively,showingbetterantifungalactivitythanthatof
thecommercialfungicidechlorothanil. Also,compound(Z)-4r(R=β-pyridyl)displayedremarkable
antifungalactivityagainstallthetestedfungi,withinhibitionratesof76.7%,82.7%,97.1%,66.3%,
74.7%,93.9%,76.7%and93.3%,respectively,showingbetterorcomparableantifungalactivitythan
thatofthecommercialfungicidechlorothanil. Besides,theE-Zisomersofthetargetoximeesters
werefoundtoshowobviousdifferencesinantifungalactivity. Theseresultsprovideanencouraging
frameworkthatcouldleadtothedevelopmentofpotentnovelantifungalagents.
Keywords: 3-carene;3-caren-5-one;3-caren-5-oneoximeester;E-Zstereoisomer;antifungalactivity
1. Introduction
3-Carene,anaturallyoccurringbicyclicmonoterpenecontainingacarbon-carbondoublebond
andagem-dimethylcyclopropanering,isaconstituentofmanyessentialoilsandturpentineoils[1,2].
Itwasreportedthattheisomericmixtureof3-careneshowedabroadspectrumofactivities,suchas
antimicrobial[3–6],anticancer[6],semiochemical[7,8],antioxidant[6,9],andfumigantactivities[10].
Becauseofitsspecialstructureandbioactiveactivities,screeningofstructurallymodified3-carene
derivatives for their bioactivity has received considerable attention. For instance, stable, potent,
andselectivesphingosine-1-phosphatereceptor1(S1P )agonistsweresuccessivelysynthesizedby
1
using(+)-3-careneasstartingmaterial[11]. Ingenoland(+)-phorbol, twocrucialnaturalproducts
withvariousbiologicalactivities,especiallyanticancer,havebeenalsosynthesizedfrominexpensive
(+)-3-carene[12–15]. Ontheotherhand,oximeestersasanimportantclassofbioactivecompounds
foragrochemicalandpharmaceuticalusewereinvestigatedextensivelybychemists. Itwasreported
that oxime esters exhibited insecticidal [16,17], herbicidal [18], antiviral [19], antitumor [20–22],
and antibacterial activities [23–25]. For example, a series of 3-ethoxy-4-hydroxybenzaldehyde
oxime esters were synthesized and evaluated for their invitro antifungal activity against three
pathogenicfungiandantibacterialactivityagainstthreebacterialstrains,andthestructure-activity
Molecules2017,22,1538;doi:10.3390/molecules22091538 www.mdpi.com/journal/molecules
MMoolleeccuulleess 22001177,, 2222,, 11553388 22 ooff 1145
was also preliminarily summarized [26]. In continuation of our interest in the bioactive properties of
relationshipwasalsopreliminarilysummarized[26]. Incontinuationofourinterestinthebioactive
natural product-based compounds [27–33], a series of novel 3-caren-5-one oxime esters were
propertiesofnaturalproduct-basedcompounds[27–33],aseriesofnovel3-caren-5-oneoximeesters
designed and synthesized by integrating bioactive oxime esters into the skeleton of 3-carene.
weredesignedandsynthesizedbyintegratingbioactiveoximeestersintotheskeletonof3-carene.
Structural characterization and antifungal evaluation of all the title compounds were carried out as
Structuralcharacterizationandantifungalevaluationofallthetitlecompoundswerecarriedoutas
well. In addition, Cu(II)HY zeolite was first employed as catalyst in the oxidative preparation of 3-
well. In addition, Cu(II)HY zeolite was first employed as catalyst in the oxidative preparation of
caren-5-one, and the E-Z stereo-isomers of 3-caren-5-one oxime were also separated for the first time
3-caren-5-one,andtheE-Zstereo-isomersof3-caren-5-oneoximewerealsoseparatedforthefirsttime
by column chromatography.
bycolumnchromatography.
2. Results and Discussion
2. ResultsandDiscussion
22..11.. SSyynntthheessiiss aanndd CChhaarraacctteerriizzaattiioonn
AAss iilllluussttrraatteeddi ninth tehSec hSecmheem1e, 31-c, a3r-ecna-r5e-no-n5e-o(2n)ew (a2s) pwreaps aprerdepbayreodx idbayt iooxniodfa3ti-ocnar eonf e3(-1c,airseonmee r(1ic,
imsoixmtuerriec) musiixntugrTe)B uHsPin(gt eTrtB-bHuPty (ltehryt-dbruotpyle rhoyxdidroe)pearsooxixdide)a nats ionxiada3n0%t iny iae ld30(%G Cyi)e.lIdn (tGhCis).p Irno ctehsiss,
pCruo(cIeI)sHs,Y C,iun(IwI)hHicYh, Cinu (wII)hiiochn sCwue(rIIe) iniocnosr pworeartee dinicnotorpHorYatzeedo liinteto, wHaYs czheoosleintea, swaahs ectehroosgeenn eaosu as
hcaettaelryosgtetnoeionucsr ecaastealtyhset tsoe liencctrievaitsye ftohre 2sedleucetitvoittyh efosrh 2a pdeu-es etole tchtiev sihtyapoef-tsheilsecmtievsiotyp oofr othuiss mmaetseorpiaolr[o3u4s]
manadtetrhieala [c3t4iv] aatniodn tchaep aacctitivyaotfiocno pcpaperacioitny toof scaotuprpaetre dioCn– tHo s[3a5tu–r3a7t]e.dA Cft–erHt h[3e5r–e3a7c]t.i oAnftwera sthceo mrepalcettieodn,
wthaiss ccaotmalpyslettceodu, ltdhiesa csailtyalbyests ecpoaurldat eedasfirloym bet hseepreaaracttieodn fsryosmte mtheb yrefiaclttriaotnio sny,satenmd cboyu lfdiltbraetrioency, calnedd
cseovueldra bleti mreecys.cled several times.

SScchheemmee 11.. SSyynnththeesissi soof f3-3c-acraerne-n5--5o-noen eoxoixmime eesteesrtse r(sZ)(-Z4)a-–44aw–4,w an,dan (Ed)-(4Ef)′-,4 4fl(cid:48)′,, 44lr(cid:48)′., 44ar:(cid:48) .R4 =a :PhR; 4=bP: hR; =4 ob-:
CRl= Pho-;C 4lc:P Rh ;=4 mc:-CRl= Pmh;- C4dl:P Rh ;=4 pd-:CRl P=h;p -4Ce:l RP h=; o4-eF: PRh= 4fo:- FR P=h p-4Ff :PRh;= 4gp:- FRP =h o;-4OgM: Re P=ho; -4OhM: Re P= ho;-M4he:
PRh=; 4oi-:M Re =P mh;-M4i:e RPh=; m4j-:M Re =P ph-M;4ej: PRh=; 4pk-:M Re =P 2h,;44-Ck:l RPh=; 42l,:4 -RC =l P2h,3;-4Cll: PRh=; 42m,3:- CRl =P ph-;C4Hm2:CRl P=hp; -4CnH: 2RC =l
cPyhc;lo4np:enRty=l;c 4yoc:l oRp e=n ctyycl;lo4hoe:xRyl=; 4cpyc: lRo h=e xαy-flu;4rypl:; R4q=: Rα- f=u αry-tlh;4ieqn:yRl; =4rα: -Rth =ie βn-yply;r4ird:yRl; =4sβ: -Rpy =r iαd-yCl;l-4βs-:
pRy=riαd-yCl;l -4βt:- pRy =r ind-yple;n4tt:yRl; 4=un: -Rp =e nettyhly;l4; u4:vR: R= =e nth-pyrl;o4pvy:l;R 4=w:n R-p =r onp-byul;t4ywl; :4Rf′: =Rn =- bpu-Ft yPlh;4; f4(cid:48)l:′:R R= = p2-,F3-PChl;;
44rl(cid:48)′:: RR == β2-,p3-yCrild;4yrl(cid:48). :R=β-pyridyl.
3-Caren-5-one oxime (3, isomeric mixture) was prepared by oximation of compound 2 with
3-Caren-5-one oxime (3, isomeric mixture) was prepared by oximation of compound 2 with
NNHH2OOHH··HHCCll iinn aa mmiixxeedd ssoollvveenntt ((EEttOOHH::HH2OO == 55::11,, vv//vv)). .SSooddiuiumm aacceettaattee wwaass aaddddeedd iinnttoo tthhee rreeaaccttiioonn
2 2
system as an additive to neutralize HCl and form a buffer system. Two stereoisomers, (Z)-3-caren-5-
systemasanadditivetoneutralizeHClandformabuffersystem. Twostereoisomers,(Z)-3-caren-5-one
one oxime ((Z)-3a) and (E)-3-caren-5-one oxime ((E)-3b), were isolated from compound 3 (3a:3b = 7:1,
oxime((Z)-3a)and(E)-3-caren-5-oneoxime((E)-3b),wereisolatedfromcompound3(3a:3b=7:1,w/w,
wG/Cw),. IGnCth).e In1H t-hNe M1HR-NspMecRtr uspmecotrfu(Zm) -o3af ,(tZh)e-3oal,e ftihnei coplerfoitnoinc (pCro-tHon) i(nCt4h-He)3 -icna rtehnee 3s-kcaerleetnoen sskheolewtoedn
4
sshigonwalesda tsiagbnoaulst 5a.t8 8aabnodutt h5e.8s8i gannadls tohfet hseigCna-lHs oafp ptheea reCd6-aHt 1a.p99pepaprmed. Hato w1.9ev9 epr,ptmhe. cHororwesepvoenr,d itnhge
6
corresponding signals of another isomer (E)-3b were shifted to 6.65 ppm and 1.50 ppm, respectively
signalsofanotherisomer(E)-3bwereshiftedto6.65ppmand1.50ppm,respectively(Figure1). Dueto
(Figure 1). Due to the hydrogen bond interaction of the hydroxyl group oxygen with the olefinic
thehydrogenbondinteractionofthehydroxylgroupoxygenwiththeolefinicproton(C -H)orthe
4
pCro-Hto,nt h(Ce4s-iHgn) aolro tfhoel eCfi6n-Hic, pthroet osingn(Cal -oHf )oilneftihneic( Ep)r-oistoomn e(Cr4a-nHd) tihne tshieg n(Ea)l-oisfotmheeCr a-nHd itnheth seig(Zna)-li soofm theer
6 4 6
Csh6-ifHte idn ttohed o(Zw)-nifsioemlde[r3 s8h].ifTtehde tsotr duocwtunrefiseoldf t[h38e]t.w Thoes tsetrreuoc-tiusroems eorfs thwee trweofu srttehreero-ciosnofmiremrse dwberyeN fuOrtEhSeYr
confirmed by NOESY spectra. In the NOESY spectrum of (Z)-3a, no peak related to the coupling of
spectra. IntheNOESYspectrumof(Z)-3a,nopeakrelatedtothecouplingofhydroxylhydrogenwith
hCy-dHrowxyals hoybdserrovgeedn, wwhitihle Ca4-pHea wkacso rorbessperovneddi,n wghtoilteh ais psepaakc ecoinrtreersapcotinodnining( tEo) -t3hbisw spasacfoeu inndter(Faicgtiuorne i2n).
4
(E)-3b was found (Figure 2).
Molecules2017,22,1538 3of15
MMoolleeccuulleess 22001177,, 2222,, 11553388 33 ooff 1144

FFFiigigguuurrreee1 11... 1 11HHH---NNNMMMRRR ssspppeeeccctttrrraaa ooofff (((ZZZ)))---333aaa aaannnddd (((EEE)))---333bbb...

Figure2.ThecouplingofC -Handhydroxylhydrogenin1H-1HNOESYspectra.
FFiigguurree 22.. TThhee ccoouupplliinngg ooff CC444--HH aanndd hhyyddrrooxxyyll hhyyddrrooggeenn iinn 11HH--11HH NNOOEESSYY ssppeeccttrraa..
TTThhheee tttaaarrrgggeeettt oooxxxiimimmeee eeessstteteerrrsss wwweeerrreee c cchhhaaarrraaaccctetteerrriziizzeeeddd bbbyyy U UUVVV-V--VVisii,ss,,I RIIRR,,,1 H11HH-N--NNMMMRRR,,,1 31133CCC---NNNMMMRRR,,, EEESSSIII---MMMSSS,,, aaannnddd
eeellleeemmmeeennntttaaalll aaannnaaalllyyysssiiisss,,, aaannnddd aaallllll ttthhheee rrreeelllaaattteeeddd ssspppeeeccctttrrraaa cccaaannn b bbeeef fofoouuunnndddi niinnt htthheeeS SSuuupppppplelleemmmeeennntttaaarrryyy M MMaaattteeerrriiiaaalllsss... IIIttt wwwaaasss
fffooouuunnnddd ttthhhaaattt ttthhheee mmmooolllaaarrr eeexxxtttiiinnnccctttiiiooonnn cccoooeeeffffiffiiccciiieeennnttt ooofff aaallllll tttaaarrrgggeeettt cccooommmpppooouuunnndddsss rrraaannngggeeeddd fffrrrooommm 333...888999 tttooo 444...444222 (((llloooggg εεε))),,,
iiimmmpppllylyyiininngggt tthhhaaattta aa c ccooonnnjjujuugggaaattteeeddds ssyyysssttteeemmme eexxxiisisstteteedddi ininnt tthhheeessseeec ccooommmpppooouuunnndddsss...I IInnn t tthhheee I IIRRR ssspppeeeccctttrrraaa,,, ttthhheee wwweeeaaakkk aaabbbsssooorrrppptttiiiooonnn
bbbaaannndddsss aaattt a aabbbooouuuttt3 33000111888c ccmmm−−−111 wwweeerrreee aaattttttrrriiibbbuuuttteeeddd tttooo ttthhheee ssstttrrreeetttccchhhiiinnnggg vvviiibbbrrraaatttiiiooonnnsss ooofff ttthhheee uuunnnsssaaatttuuurrraaattteeeddd CCC–––HHH iiinnn ttthhheee
333---cccaaarrreeennneee m mmoooiiieeetttyyy...T TThhheees sstrttroroonnnggga aabbbssosoorrprpptittoiioonnnb bbaaannndddsssa aattta aabbbooouuuttt1 17173738388c mccmm−−−111 wwweeerrreee aaassssssiiigggnnneeeddd tttooo ttthhheee vvviiibbbrrraaatttiiiooonnnsss ooofff
CCC===OOO iiinnn ttthhheee eeesssttteeerrr m mmoooiiieeetttyyy...T TThhheeem mmooodddeeerrraaatetteea aabbbssosoorprrpptittoiioonnnp ppeaeeakakksssa taatat baabobououut1tt 61146694499c mccmm−−1−11 wwweeerrreee ddduuueee tttooo ttthhheee vvviiibbbrrraaatttiiiooonnnsss
ooofff CCC===NNN... IIInnn ttthhheee 111HHH---NNNMMMRRR ssspppeeeccctttrrraaa,,, ttthhheee ppprrroootttooonnnsss ooofff bbbeeennnzzzeeennneee rrriiinnnggg ssshhhooowwweeeddd sssiiigggnnnaaalllsss aaattt 7 77.1..11000–––888..2.22000 p pppppmmm... TTThhheee
ooollleeefiffiinnniiciccp pprrroootttooonnnssso ooffft tthhheee3 33---cccaaarrreeennneees sscccaaaffffffoooldlldds sshhhooowwweeeddds ssiigiggnnnaaalsllssa aattta aabbbooouuuttt6 66.1..11000p pppppmmmf ffooorrr t tthhheee ( ((ZZZ)))---iiisssooommmeeerrrsss a aannnddd t tthhheee
(((EEE)))---isiissooommmeeerrsrsss hssohhwoowwedeeddsi gssniigganlnsaaallsst aaabtto uaatbbo6o.uu6tt0 p66..p66m00 .ppTpphmme..p rTTohhtoeen psprrbooottnoodnnessd bbtooonntdhdeeedds a tttuoo r atththeeed sscaaattruubrroaanttseeddd isccpaalrrabbyooenndss
sddigiissnppalllaasyyieenddt sshiieggnnraaanllssg iienn otthhfee0 .rr5aa0nn–gg3ee. 0 oo0ff p00..p55m00––.33T..00h00e pp1pp3mmC-.. N TThMheeR 1133CCsp--NNecMMtraRR ossfppteehccettrrataa oorgff tethhteec ottaamrrggpeeottu ccnoomdmsppsoohuuonnwddessd sshhpooewwakeesdd
fppoeeraatkkhsse ffooolrre fitthhneei coolcleeaffriinbnoiiccn ccsaaorrbbfoothnness 3oo-ffc ttahhreee n33e--ccmaarroeeinneeet ymmaootii1eet1tyy7 .aa9tt2 11–111771..999.220––511p119p9..m0055 (ppCpp4mm)a ((nCCd44))1 aa4nn7dd.4 911–441774..44999.7––41144p99p..77m44 pp(Cppm3m)
f((oCCr33)t) h ffooerr( tZthh)ee- i ((sZZo))m--iisseoormsm,eehrrossw,, hheoovwweree,vvteehrre,, ttchhoeer rcceoosrrprreeossnppdooinnnddgiinnsiggg ssniiagglnnsaaflloss r ffoo(Err )((-EEi)s)--oiissmoomemreserrsssh ssohhwoowwedeedda taaatt baabobououuttt1 11111333.2..22000( (C(CC444)))
ppppppmmm a aannnddd 1 11555333.0..00333p pppppmmm( (C(CC333)))... TTThhheee ooottthhheeerrr sssaaatttuuurrraaattteeeddd cccaaarrrbbbooonnnsss dddiiisssppplllaaayyyeeeddd sssiiigggnnnaaalllsss iiinnn ttthhheee rrreeegggiiiooonnn ooofff 1 11333.5..55999–––555555..9.99444
ppppppmmm... TTThhheee ooottthhheeerrr sssiiigggnnnaaalll pppeeeaaakkksss wwweeerrreee c ccooorrrrrreeellalaattteeeddd t ttooot ththheeec ccaaarrrbbbooonnnssso oofffC CC===OOO,,,C CC===NNN,,, aaannnddd ttthhheee b bbeeennnzzzeeennneee r rriininnggg... TTThhheee
mmmooollleeecccuuulllaaarrr wwweeeiiiggghhhtttsss ooofff ttthhheee iiinnnttteeerrrmmmeeedddiiiaaattteeesss aaannnddd tttaaarrrgggeeettt oooxxxiiimmmeee eeesssttteeerrrsss wwweeerrreee cccooonnnffifiirrrmmmeeeddd bbbyyy tthhtheee EEESSSII--IMM-MSSS.. .
2.2. AntifungalActivity
22..22.. AAnnttiiffuunnggaall AAccttiivviittyy
Theantifungalactivitiesofthetargetcompounds(Z)-4a–4wand(E)-4f(cid:48)wereevaluatedbyinvitro
TThhee aannttiiffuunnggaall aaccttiivviittiieess ooff tthhee ttaarrggeett ccoommppoouunnddss ((ZZ))--44aa––44ww aanndd ((EE))--44ff′′ wweerree eevvaalluuaatteedd bbyy iinn
methodagainstfusariumwiltoncucumber(Fusariumoxysporumf. sp.cucumerinum),speckleonpeanut
vviittrroo mmeetthhoodd aaggaaiinnsstt ffuussaarriiuumm wwiilltt oonn ccuuccuummbbeerr ((FFuussaarriiuumm ooxxyyssppoorruumm ff.. sspp.. ccuuccuummeerriinnuumm)),, ssppeecckkllee oonn
(Cercosporaarachidicola),appleringrot(Physalosporapiricola),tomatoearlyblight(Alternariasolani),wheat
ppeeaannuutt ((CCeerrccoossppoorraa aarraacchhiiddiiccoollaa)),, aappppllee rriinngg rroott ((PPhhyyssaalloossppoorraa ppiirriiccoollaa)),, ttoommaattoo eeaarrllyy bblliigghhtt ((AAlltteerrnnaarriiaa
scab(Gibberellazeae),ricesheathblight(Rhizoeotniasolani),cornsouthernleafblight(Bipolarismaydis),
ssoollaannii)),, wwhheeaatt ssccaabb ((GGiibbbbeerreellllaa zzeeaaee)),, rriiccee sshheeaatthh bblliigghhtt ((RRhhiizzooeeoottnniiaa ssoollaannii)),, ccoorrnn ssoouutthheerrnn lleeaaff bblliigghhtt
andwatermelonanthracnose(Colleterichumorbicalare)at50µg/mL.TheresultsarelistedinTable1.
((BBiippoollaarriiss mmaayyddiiss)),, aanndd wwaatteerrmmeelloonn aanntthhrraaccnnoossee ((CCoolllleetteerriicchhuumm oorrbbiiccaallaarree)) aatt 5500 µµgg//mmLL.. TThhee rreessuullttss aarree
lliisstteedd iinn TTaabbllee 11..
Molecules2017,22,1538 4of15
Table1.Antifungalactivityofthetargetcompounds(Z)-4a–4wand(E)-4f(cid:48)at50µg/mL.
RelativeInhibitionRate(%)againsttheTestedFungi
Compounds
F.oxysporumf.sp.cucumerinum C.arachidicola P.piricola A.solani G.zeae R.solani B.myadis C.orbicalare
(Z)-4a(R=Ph) 28.8 35.0 69.4 13.7 21.8 0 32.2 43.3
(Z)-4b(R=o-ClPh) 16.3 30.0 0 0 21.8 18.3 23.9 30.5
(Z)-4c(R=m-ClPh) 22.5 0 44.4 0 21.8 17.1 26.7 33.1
(Z)-4d(R=p-ClPh) 28.8 0 28.8 0 19.8 0 29.4 33.1
(Z)-4e(R=o-FPh) 31.9 45.0 41.3 35.9 37.5 35.0 26.7 45.9
(Z)-4f(R=p-FPh) 25.6 15.0 30.7 0.0 15.9 0 26.7 23.8
(Z)-4g(R=o-OMePh) 25.6 0 60.0 21.1 13.9 0 26.7 35.6
(Z)-4h(R=o-MePh) 31.9 50.0 28.8 21.1 29.6 38.6 29.4 43.3
(Z)-4i(R=m-MePh) 19.4 15.0 85.0 0 12.0 0 23.9 0
(Z)-4j(R=p-MePh) 38.1 20.0 81.9 24.8 17.8 0 35.0 53.6
(Z)-4k(R=2,4-ClPh) 28.8 55.0 16.3 13.7 17.8 18.3 23.9 53.6
(Z)-4l(R=2,3-ClPh) 25.6 15.0 28.8 17.4 19.8 0 21.1 43.3
(Z)-4m(R=p-CH2ClPh) 56.9 20.0 41.3 0 19.8 0 21.1 40.8
(Z)-4n(R=cyclo-pentyl) 22.5 35.0 0 13.7 19.8 0 23.9 51.0
(Z)-4o(R=cyclo-hexyl) 25.6 30.0 28.8 21.1 15.9 16.0 23.9 40.8
(Z)-4p(R=α-furyl) 60.0 64.5 77.7 53.8 36.5 54.6 43.3 54.4
(Z)-4q(R=α-thienyl) 48.9 37.3 87.4 41.3 33.5 42.1 33.8 48.9
(Z)-4r(R=β-pyridyl) 76.7 82.7 97.1 66.3 74.7 93.9 76.7 93.3
(Z)-4s(R=α-Cl-β-pyridyl) 15.6 37.3 55.2 41.3 54.1 63.6 24.3 21.1
(Z)-4t(R=n-pentyl) 21.1 19.1 58.4 35.0 48.2 67.1 24.3 21.1
(Z)-4u(R=n-ethyl) 15.6 19.1 58.4 28.8 48.2 36.8 29.0 21.1
(Z)-4v(R=n-propyl) 15.6 28.2 32.6 41.3 57.1 54.6 24.3 21.1
(Z)-4w(R=n-butyl) 15.6 19.1 51.9 22.5 18.8 18.9 19.5 21.1
(E)-4f(cid:48)(R=p-FPh) 60.0 64.5 87.4 53.8 65.9 76.1 76.7 54.4
(Z)-3a 15.6 23.6 51.9 35.0 18.8 24.3 24.3 26.7
(E)-3b 15.6 23.6 51.9 22.5 18.8 27.9 19.5 21.1
2 21.1 19.1 45.5 16.3 24.7 18.9 24.3 15.6
Chlorothanil 100 73.3 75.0 73.9 73.1 96.1 90.4 91.3
Molecules2017,22,1538 5of15
Itwasfoundthat,at50µg/mL,allthetargetcompoundspresentedobviouslydifferentantifungal
activity against the eight tested fungi. Compared with the intermediates 2, 3a and 3b, some of
the target compounds showed enhanced activities after esterification. On the whole, most of the
targetcompoundsexhibitedbestantifungalactivityagainstP.piricola,inwhichcompounds(Z)-4r
(R= β-pyridyl), (Z)-4q(R= α-thienyl), (E)-4f(cid:48) (R=p-FPh), (Z)-4i(R=m-MePh), (Z)-4j(R=p-Me
Ph), and(Z)-4p(R= α-furyl)hadinhibitionratesof97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and77.7%,
respectively, showingbetterantifungalactivitythanthatofthecommercialfungicidechlorothanil
withtheinhibitionrateof75.0%. Itwasalsofoundthatcompound(Z)-4r(R=β-pyridyl)displayed
remarkableantifungalactivityagainstallthetestedfungi,withinhibitionratesof76.7%,82.7%,97.1%,
66.3%,74.7%,93.9%,76.7%and93.3%,respectively,showingbetterorcomparableantifungalactivity
thanthatofthecommercialfungicidechlorothanil. Therefore,compound(Z)-4r(R=β-pyridyl)isa
leadcompoundworthyoffurtherinvestigation. Furthermore,itwasfoundthat(E)-isomer4f(cid:48) (R=p-F
Ph)exhibitedmuchbetterantifungalactivitythanthecorresponding(Z)-isomer4f(R=p-FPh)against
allthetestedfungi. Forinstance,(E)-isomer4f(cid:48) (64.5%)showed4.3timesthatof4f(Z)-isomer(15.0%)
againstC.arachidicola,andthetwoisomersdisplayed76.1%and0.0%inhibitionrates,respectively,
againstR.solani. TheobviousdifferenceinantifungalactivitybetweenE-Zisomersisverymeaningful
andrequiresfurtherstudiesinphotoisomerizationanddrugresistance.
3. ExperimentalSection
3.1. GeneralInformation
TheGCanalysiswasperformedonanAgilent6890GC(AgilentTechnologiesInc.,SantaClara,
CA,USA)equippedwithaHP-1(30m,0.530mm,0.88µm)column. IRspectrawererecorded(KBr
pelletmethod)onaNicoletiS50FT-IRspectrometer(ThermoScientificCo.,Ltd.,Madison,WI,USA).
NMRspectra(including1H-NMR,13C-NMR,NOESY)wererecordedinCDCl solventonaBruker
3
AvanceIIIHD600MHzspectrometer(BrukerCo.,Ltd.,Zurich,Switzerland)andchemicalshiftsare
expressedinppm(δ)downfieldrelativetoTMSasaninternalstandard. MSspectrawereobtained
by means of the electrospray ionization (ESI) method on TSQ Quantum Access MAX HPLC-MS
instrument (Thermo Scientific Co., Ltd., Waltham, MA, USA). Elemental analyses were measured
using aPE 2400II elementalanalyzer (Perkin-ElmerInstrumentsCo., Ltd., USA).The UVspectra
weremeasuredonaShimadzuUV-1800spectrophotometer(ShimadzuCorp.,Kyoto,Japan). Melting
pointsweredeterminedonaMP420automaticmeltingpointapparatus(HanonInstrumentsCo.,Ltd.,
Jinan,China)andwerenotcorrected. UltrasonicirradiationwascarriedoutonXO-SM50ultrasonic
microwavereactionsystem(NanjingXianouInstrumentManufacturingCo.,Ltd.,Nanjing,China).
3-Carene (GC purity 98%, isomeric mixture) was provided by Wuzhou Pine Chemicals Co., Ltd.
(Wuzhou,Guangxi,China). The7ÅHYzeolitewaspurchasedfromNankaiUniversityCatalystCo.,
Ltd. (Tianjin,China). Otherreagentswerepurchasedfromcommercialsuppliersandusedasreceived.
3.2. PreparationofCatalyst
Cu(II)HYzeolitecatalystusedforthesynthesisof3-caren-5-onewaspreparedbytheincipient
wetness method [39]. HY zeolite with pore diameter of 7 Å was dried at 120 ◦C 3 h under air
atmosphere. Then,asolutionofCu(NO ) ·3H O(5.7g)indeionizedwaterbasedonthesaturated
3 2 2
waterabsorptionamountofthezeolite(10.0g)wasaddeddropwisetothedriedzeolite,withconstant
stirringandgrinding. Theresultingmixturewasagedfor24h,andthendriedinvacuumat120◦Cfor
2h. Thepowdersamplewascalcinatedat550◦Cfor4hunderairatmosphere.
3.3. Synthesisof3-Caren-5-One(2)
3-Carene(10mL,63mmol),Cu(II)HYzeolitecatalyst(2.7g)andCH CN(20mL)weremixedand
3
thenirradiatedunderultrasonicwavefor40min. Whenthemixturewasheatedto45◦C,amixed
solutionof40mLtert-butylhydroperoxide(70%inwater,wt%)(288mmol)and20mLCH CNwas
3
Molecules2017,22,1538 6of15
addedtothereactionsystembythewayofconstantflowingatarateof1mL/min. Afterwards,the
reactionmixturewasstirredfor18hat45◦C.Whenthereactionwascompleted,thereactionmixture
wascooledtoroomtemperatureandappropriateamountofNa S O wasaddedintoittodestroythe
2 2 3
unreactedtert-butylhydroperoxide. ThesolventCH CNwasremovedbyvacuumdistillation,and
3
theresiduewasthenextractedthreetimeswithEtOAc. Thecombinedorganicphasewaswashed
withsaturatedsodiumchlorideanddeionizedwater,respectively,anddriedoverwithanhydrous
Na SO . After the EtOAc was removed in vacuum, the crude product was purified by silica gel
2 4
columnchromatography(EtOAc−petroleumether=1:30,v/v)toobtainpaleyellowliquidcompound
2. Yield20%. UV-Vis(EtOH)λ (logε): 226.50(4.4.16)nm;IR(thinfilm,cm−1): 3029(w,=C-H),1655
max
(s,C=O);1H-NMRδ=5.83(s,1H,C -H),2.64(dd,J=20.4,8.5Hz,1H,C -H ),2.33(d,J=20.8Hz,1H,
4 2 a
C -H ),1.87(s,3H,C -CH ),1.56(d,J=7.8Hz,1H,C -H),1.45(t,J=8.0Hz,1H,C -H),1.19(s,3H,
2 b 3 3 6 1
C -CH ),1.04(s,3H,C -CH );13C-NMRδ=196.67(C ),158.96(C ),126.40(C ),32.85(C ),28.43(C ),
7 3 7 3 5 3 4 6 9
27.87(C ),25.86(C ),23.68(C ),22.57(C ),14.38(C );ESI-MSm/z: 151.17[M+H]+. Anal. Calcd. For
2 1 10 7 8
C H O(150.22): C,79.96;H,9.39. Found: C,79.85;H,9.36.
10 14
3.4. Synthesisof3-Caren-5-OneOxime(3)
3-Caren-5-one(1.5g,10mmol),NH OH·HCl(1.04g,15mmol),andNaOAc(4.08g,30mmol)
2
weredissolvedinamixedsolvent(EtOH:H O=5:1,v/v). Thereactionmixturewasstirredat80◦C
2
for 3 h. The reaction process was monitored by TLC. When 3-carene-5-one was fully reacted, the
mixturewascooledtoroomtemperature. AfterthesolventEtOHwasremovedbyrotaryevaporation,
theresiduewasextractedbyEtOAc. TheseparatedorganicphasewaswashedwithsaturatedNaCl
solutionthreetimes,andconcentratedunderreducedpressuretoobtainthecrudeproduct,whichwas
purifiedbysilicagelcolumnchromatographyusingamixedsolvent(EtOAc−petroleumether=1:60,
v/v)aseluent.
(Z)-3-Caren-5-oneoxime((Z)-3a)wasobtainedasawhiteneedlecrystal. Yield63.5%,m.p.: 96.7–98.1◦C.
UV-Vis(EtOH)λ (logε): 239.70(4.28)nm;IR(KBr,cm−1): 3464–3078(s,br,O-H),3033(w,=C-H),
max
1659(m,C=N),1614(m);1H-NMRδ=9.03(s,1H,OH),δ5.87(s,1H,C -H),2.45(dd,J=20.0,8.2Hz,
4
1H,C -H ),2.12(d,J=20.0Hz,1H,C -H ),1.97(d,J=8.3Hz,1H,C -H),1.76(s,3H,C -CH ),1.23
2 a 2 b 6 3 3
(s,3H,C -CH ),1.19(t,J=8.3Hz,1H,C -H),0.89(s,3H,C -CH );13C-NMRδ=155.00(C ),142.27
7 3 1 7 3 5
(C ),119.32(C ),27.97(C ),27.08(C ),23.39(C ),22.37(C ),20.71(C ),19.67(C ),14.59(C );ESI-MS
3 4 6 9 2 1 10 7 8
m/z: 166.14[M+H]+. Anal. Calcd. ForC H NO(165.23): C,72.69;H,9.15;N,8.48. Found: C,72.71;
10 15
H,9.17;N,8.49.
(E)-3-Caren-5-oneoxime((E)-3b)wasobtainedasawhiteplate-likecrystal. Yield3%,m.p.: 73.5–75.0◦C.
UV-Vis(EtOH)λ (logε): 235.80(3.89)nm;IR(KBr,cm−1): 3432–3081(s,br,O-H),3015(w,=C-H),
max
1644(m,C=N),1608(m);1H-NMRδ=8.98(s,1H,OH),6.64(s,1H,C -H),2.48(dd,J=20.4,8.0Hz,
4
1H,C -H ),2.16(d,J=20.5Hz,1H,C -H ),1.82(s,3H,C -CH ),1.49(d,J=8.7Hz,1H,C -H),1.19
2 a 2 b 3 3 6
(t,J=8.3Hz,1H,C -H),1.13(s,3H,C -CH ),0.88(s,3H,C -CH );13C-NMRδ=152.05(C ),147.32
1 7 3 7 3 5
(C ),112.59(C ),28.03(C ),27.71(C ),23.86(C ),23.54(C ),21.82(C ),19.61(C ),14.15(C );ESI-MS
3 4 6 9 2 1 10 7 8
m/z: 166.14[M+H]+. Anal. Calcd. ForC H NO(165.23): C,72.69;H,9.15;N,8.48. Found: C,72.60;
10 15
H,9.18;N,8.46.
3.5. GeneralProcedureforSynthesisof3-Caren-5-OneOximeEsters(Z)-4a–4w,(E)-4f(cid:48),4l(cid:48),4r(cid:48)
Asolutionofacylchloride(1.2mmol)inCH Cl (3mL)wasaddedslowlytoasolutionof(Z)-
2 2
or (E)-3-carene-5-one oxime (1 mmol) and triethylamine in CH Cl (5 mL) with ice-water cooling.
2 2
ThereactionprocesswasmonitoredbyTLC.Uponcompletion,5mLdeionizedwaterwasaddedto
thereactionmixturetodestroytheunreactedacylchloride. Then,theorganiclayerwasseparated,
washedwithdeionizedwaterthreetimes,andconcentratedinvacuum. Thecrudeproductwasfurther
purifiedbysilicagelchromatographytoaffordthetargetcompounds(Z)-4a–4w,and(E)-4f(cid:48),4l(cid:48),4r(cid:48).
Molecules2017,22,1538 7of15
Onlythree(E)-oximeesters,i.e.,(E)-4f(cid:48),4l(cid:48),4r(cid:48),werereportedinthisstudybecauseoftheverylow
yieldof(E)-3b.
(Z)-3-Caren-5-oneO-(benzoyl)oxime((Z)-4a). Paleyellowsolid. Yield: 65.4%,m.p.: 97.4–98.7◦C.UV-Vis
(EtOH)λ (logε): 257.40(4.34)nm,236.70(4.25)nm;IR(KBr,cm−1): 3069(w),3015(w,Ar-H,=C-H),
max
1739(s,C=O),1658(m,C=N),1602(w),1581(s),1495(w),1456(m,Ar);1H-NMRδ=8.10(d,J=7.1Hz,
2H,C -H,C -H),7.59(t,J =7.4Hz,1H,C -H),7.47(t,J =7.8Hz,2H,C -H,C -H),6.17(s,1H,
13 17 15 14 16
C -H),2.56(dd,J=20.2,8.4Hz,1H,C -H ),2.21(d,J=19.5Hz,1H,C -H ),2.05(d,J=8.2Hz,1H,
4 2 a 2 b
C -H),1.85(s,3H,C -CH ),1.34(d,J=7.8Hz,1H,C -H),1.30(s,3H,C -CH ),0.94(s,3H,C -CH );
6 3 3 1 7 3 7 3
13C-NMR δ = 164.12 (C ), 161.89 (C ), 147.97 (C ), 133.02 (C ), 129.60 (C ), 129.53 (C and C ),
11 5 3 15 12 13 17
128.49(C andC ),118.38(C ),28.09(C ),27.15(C ),23.77(C ),23.08(C ),21.68(C ),21.32(C ),
14 16 4 6 9 2 1 10 7
14.59(C );ESI-MSm/z: 270.09[M+H]+. Anal. Calcd. ForC H NO (269.34): C,75.81;H,7.11;N,
8 17 19 2
5.20. Found: C,75.79;H,7.12;N,5.21.
(Z)-3-Caren-5-oneO-(2-chlorobenzoyl)oxime((Z)-4b). Whitesolid. Yield: 74.0%,m.p.: 116.3–117.8◦C.
UV-Vis(EtOH)λ (logε): 253.50(4.23)nm. IR(KBr,cm−1): 3048(w),3012(w,Ar-H,=C-H),1726
max
(s,C=O),1652(m, C=N),1581(m), 1464(w, Ar); 1H-NMRδ=7.88(dd, J =7.8, 1.6Hz, 1H,C -H),
17
7.47(dd,J=8.0,1.4Hz,1H,C -H),7.44(td,J=8.1,7.6,1.6Hz,1H,C -H),7.35(td,J=7.6,1.4Hz,
14 15
1H,C -H),6.14(s,1H,C -H),2.54(dd,J=20.3,8.3Hz,1H,C -H ),2.21(d,J=20.3Hz,1H,C -H ),
16 4 2 a 2 b
2.08(d,J=8.1Hz,1H,C -H),1.85(s,3H,C -CH ),1.29(t,J=8.2Hz,1H,C -H),1.22(s,3H,C -CH ),
6 3 3 1 7 3
0.94 (s, 3H, C -CH ); 13C-NMR δ = 164.06 (C ), 162.31 (C ), 148.35 (C ), 133.30 (C ), 132.55 (C ),
7 3 11 5 3 12 15
131.70(C ),130.91(C ),130.03(C ),126.67(C ),118.22(C ),28.08(C ),27.21(C ),23.77(C ),23.13
13 17 14 16 4 6 9 2
(C ),21.98(C ),21.43(C ),14.56(C );ESI-MSm/z: 304.07[M+H]+. Anal. Calcd. ForC H ClNO
1 10 7 8 17 18 2
(303.78): C,67.21;H,5.97;N,4.61. Found: C,67.25;H,5.93;N,4.62.
(Z)-3-Caren-5-oneO-(3-chlorobenzoyl)oxime((Z)-4c). Whitesolid. Yield: 80.3%,m.p.: 137.3–138.1◦C.
UV-Vis(EtOH)λ (logε): 259.90(4.08)nm,229.80(4.07)nm;IR(KBr,cm−1): 3084(w),3024(w,Ar-H,
max
=C-H),1741(s, C=O),1652(m, C=N),1581(m), 1491(w, Ar);1H-NMRδ=8.07(s, 1H,C -H),7.98
13
(d,J=7.8Hz,1H,C -H),7.56(d,J=8.0Hz,1H,C -H),7.42(t,J=7.9Hz,1H,C -H),6.16(s,1H,
17 15 16
C -H),2.57(dd,J=20.3,8.4Hz,1H,C -H ),2.22(d,J=20.3Hz,1H,C -H ),2.02(d,J=8.2Hz,1H,
4 2 a 2 b
C -H),1.86(s,3H,C -CH ),1.35(t,J=8.4Hz,1H,C -H),1.32(s,3H,C -CH ),0.94(s,3H,C -CH ).
6 3 3 1 7 3 7 3
13C-NMRδ=162.94(C ),162.32(C ),148.54(C ),134.66(C ),133.07(C ),131.31(C ),129.85(C ),
11 5 3 12 15 14 16
129.65(C ),127.62(C ),118.12(C ),28.03(C ),27.16(C ),23.80(C ),23.11(C ),21.80(C ),21.35
13 17 4 6 9 2 1 10
(C ),14.59(C );ESI-MSm/z: 304.05[M+H]+. Anal. Calcd. ForC H ClNO (303.78): C,67.21;H,
7 8 17 18 2
5.97;N,4.61. Found: C,67.23;H,5.98;N,4.60.
(Z)-3-Caren-5-oneO-(4-chlorobenzoyl)oxime((Z)-4d). Whitesolid. Yield: 78.6%,m.p.: 149.9–151.3◦C.
UV-Vis(EtOH)λ (logε): 258.80(4.32)nm,245.90(4.32)nm;IR(KBr,cm−1): 3066(w),3024(w,Ar-H,
max
=C-H),1736(s,C=O),1659(m,C=N),1596(m),1578(m),1486(m,Ar);1H-NMRδ=8.03(d,J=8.4Hz,
2H,C -H,C -H),7.45(d,J=8.4Hz,2H,C -H,C -H),6.16(s,1H,C -H),2.56(dd,J=20.2,8.3Hz,
13 17 14 16 4
1H,C -H ),2.22(d,J=20.3Hz,1H,C -H ),2.01(d,J=8.1Hz,1H,C -H),1.85(s,3H,C -CH ),1.34
2 a 2 b 6 3 3
(t,J=8.2Hz,1H,C -H),1.29(s,3H,C -CH ),0.94(s,3H,C -CH );13C-NMRδ=163.34(C ),162.15
1 7 3 7 3 11
(C ),148.32(C ),139.52(C ),130.88(C ),128.89(C ,C ),128.02(C ),118.22(C ),28.10(C ),27.15
5 3 15 12 13 14 15 3 6
(C ), 23.79 (C ), 23.13 (C ), 21.77 (C ), 21.32 (C ), 14.58 (C ); ESI-MS m/z: 304.04 [M + H]+. Anal.
9 2 1 10 7 8
Calcd. ForC H ClNO (303.78): C,67.21;H,5.97;N,4.61. Found: C,67.23;H,5.95;N,4.63.
17 18 2
(Z)-3-Caren-5-oneO-(2-fluorobenzoyl)oxime((Z)-4e). Whitesolid. Yield: 76.9%,m.p.: 128.7–131.2◦C.
UV-Vis(EtOH)λ (logε): 257.60(4.29)nm,224.70(4.29)nm;IR(KBr,cm−1): 3057(w),3009(w,Ar-H,
max
=C-H),1736(s,C=O),1650(m,C=N),1608(m),1575(m),1486(m),1453(m,Ar);1H-NMRδ=8.07
(td, J = 7.5, 1.8 Hz, 1H, C -H), 7.57–7.52 (m, 1H, C -H), 7.25 (td, J = 7.7, 1.1 Hz, 1H, C -H), 7.16
17 15 16
(ddd,J=10.7,8.3,0.9Hz,1H,C -H),6.15(s,1H,C -H),2.55(dd,J=20.3,8.4Hz,1H,C -H ),2.21
14 4 2 a
(d,J=20.3Hz,1H,C -H ),2.12(d,J=8.1Hz,1H,C -H),1.85(s,3H,C -CH ),1.31(t,J=7.9Hz,1H,
2 b 6 3 3
C -H),1.26(s,3H,C -CH ),0.93(s,3H,C -CH ). 13C-NMRδ=162.29(C ),160.83(C ),148.32(C ),
1 7 3 7 3 11 5 3
Molecules2017,22,1538 8of15
134.61(C ),134.55(C ),132.63(C ),124.13(C ),118.23(C ),117.02(C ),116.87(C ),27.90(C ),
15 17 16 12 4 13 14 6
27.24(C ),23.78(C ),23.13(C ),21.88(C ),21.45(C ),14.56(C );ESI-MSm/z: 288.08[M+H]+. Anal.
9 2 1 10 7 8
Calcd. ForC H FNO (287.33): C,71.06;H,6.31;N,4.87. Found: C,71.10;H,6.30;N,4.85.
17 18 2
(Z)-3-Caren-5-oneO-(4-fluorobenzoyl)oxime((Z)-4f). Whitesolid. Yield: 65.2%,m.p.: 133.2–135.0◦C.
UV-Vis(EtOH)λ (logε): 257.00(4.29)nm,229.10(4.26)nm;IR(KBr,cm−1): 3041(w),3018(w,Ar-H,
max
=C-H),1748(s,C=O),1659(m,C=N),1602(m),1581(m),1507(m,Ar);1H-NMRδ: 8.11(dd,J=8.9,
5.4Hz,2H,C -H,C -H),7.15(t,J=8.7Hz,2H,C -H,C -H),6.16(s,1H,C -H),2.56(dd,J=20.3,
13 17 14 16 4
8.4Hz,1H,C -H ),2.22(d,J=20.3Hz,1H,C -H ),2.02(d,J=8.2Hz,1H,C -H),1.85(s,3H,C -CH ),
2 a 2 b 6 3 3
1.34 (t, J = 8.2 Hz, 1H, C -H), 1.30 (s, 3H, C -CH ), 0.94 (s, 3H, C -CH ); 13C-NMR δ: 166.63 (C ),
1 7 3 7 3 11
164.95(C ),163.23(C ),162.01(C ),148.19(C ),132.07(C orC ),132.01(C orC ),118.27(C ),
5 15 12 3 13 17 13 17 4
115.79(C orC ),115.64(C orC ),28.11(C ),27.15(C ),23.78(C ),23.12(C ),21.73(C ),21.32
14 16 14 16 6 9 2 1 10
(C ),14.59(C );ESI-MSm/z: 288.07[M+H]+. Anal. Calcd. ForC H FNO (287.33): C,71.06;H,
7 8 17 18 2
6.31;N,4.87. Found: C,71.03;H,6.29;N,4.86.
(Z)-3-Caren-5-oneO-(2-methoxybenzoyl)oxime((Z)-4g). Whitesolid. Yield: 65.0%,m.p.: 123.9–125.5◦C.
UV-Vis(EtOH)λ (logε): 254.50(4.38)nm;IR(KBr): 3054(w),3006(w,Ar-H,=C-H),1724(s,C=O),
max
1656(m,C=N),1599(m),1581(m),1489(m),1462(m,Ar);1H-NMRδ=7.85(dd,J=7.7,1.8Hz,1H,
C -H),7.48(td,J=9.0,8.2,1.8Hz,1H,C -H),7.04–6.99(m,1H,C -H),7.01–6.97(m,1H,C -H),
17 15 16 14
6.15(s,1H,C -H),3.89(s,3H,O-CH ),2.53(dd,J=20.2,8.3Hz,1H,C -H ),2.20(d,J=20.2Hz,1H,
4 3 2 a
C -H ),2.08(d,J=8.1Hz,1H,C -H),1.84(s,3H,C -CH ),1.29(t,J=8.1Hz,1H,C -H),1.23(s,3H,
2 b 6 3 3 6
C -CH ),0.93(s,3H,C -CH );13C-NMRδ=164.58(C ),161.72(C ),158.98(C ),147.53(C ),133.45
7 3 7 3 11 5 13 3
(C ),131.79(C ),120.20(C ),119.68(C ),118.58(C ),111.97(C ),55.94(C ),28.17(C ),27.21(C ),
15 17 12 16 4 14 18 6 9
23.73(C ),23.21(C ),21.70(C ),21.30(C ),14.56(C );ESI-MSm/z: 300.01[M+H]+. Anal. Calcd. For
2 1 10 7 8
C H NO (299.36): C,72.22;H,7.07;N,4.68. Found: C,72.17;H,7.04;N,4.71.
17 21 2
(Z)-3-Caren-5-oneO-(2-methylbenzoyl)oxime((Z)-4h).Whitesolid.Yield:65%,m.p.:64.7–67.5◦C.UV-Vis
(EtOH)λ (logε): 255.80(4.42)nm;IR(KBr,cm−1): 3048(w),3015(w,Ar-H,=C-H),1748(s,C=O),
max
1653(m,C=N),1605(w),1581(m),1486(w),1453(m,Ar);1H-NMRδ=7.92(d,J=6.8Hz,1H,C -H),
17
7.42(t,J=7.5Hz,1H,C -H),7.28(d,J=7.6Hz,1H,C -H),7.26(d,J=7.5Hz,1H,C -H),6.16(s,1H,
15 16 14
C -H),2.66(s,3H,C -CH ),2.54(dd,J=20.6,8.7Hz,1H,C -H ),2.20(d,J=20.3Hz,1H,C -H ),2.00
4 13 3 2 a 2 b
(d,J=8.2Hz,1H,C -H),1.85(s,3H,C -CH ),1.30(t,J=8.2Hz,1H,C -H),1.25(s,3H,C -CH ),0.94
6 3 3 1 7 3
(s,3H,C -CH );13C-NMRδ=165.43(C ),161.56(C ),147.75(C ),140.06(C ),131.95(C ),131.67
7 3 11 5 3 13 15
(C ),130.30(C ),129.17(C ),125.70(C ),118.49(C ),28.08(C ),27.13(C ),23.74(C ),23.02(C ),
12 17 14 16 4 6 9 2 1
21.72(C andC ),21.41(C ),14.61(C );ESI-MSm/z: 284.12[M+H]+. Anal. Calcd. ForC H NO
10 18 7 8 18 21 2
(283.36): C,76.29;H,7.47;N,4.94. Found: C,76.21;H,7.50;N,4.90.
(Z)-3-Caren-5-oneO-(3-methylbenzoyl)oxime((Z)-4i). Whitesolid. Yield: 70.0%,m.p.: 131.8–133.2◦C.
UV-Vis(EtOH)λ (logε): 258.30(4.31)nm;IR(KBr,cm−1): 3054(w),3021(w,Ar-H,=C-H),1736
max
(s,C=O),1650(m,C=N),1572(m),1453(m,Ar);1H-NMRδ=7.93(s,1H,C -H),7.89(d,J=7.6Hz,
13
1H,C -H),7.39(d,J=7.6Hz,1H,C -H),7.35(t,J=7.6Hz,1H,C -H),6.16(s,1H,C -H),2.56(dd,
17 15 16 4
J=19.9,8.1Hz,1H,C -H ),2.41(s,3H,C -CH ),2.21(d,J=20.3Hz,1H,C -H ),2.05(d,J=8.2Hz,
2 a 14 3 2 b
1H,C -H),1.85(s,3H,C -CH ),1.33(t,J=8.3Hz,1H,C -H),1.31(s,3H,C -CH ),0.94(s,3H,C -CH );
6 3 3 1 7 3 7 3
13C-NMRδ=164.29(C ),161.83(C ),147.93(C ),138.29(C ),133.80(C ),130.22(C ),129.48(C ),
11 5 3 14 15 12 13
128.36(C ),126.58(C ),118.39(C ),28.03(C ),27.15(C ),23.78(C ),23.02(C ),21.62(C ),21.35
16 17 4 6 9 2 1 18
(C ),21.31(C ),14.60(C );ESI-MSm/z: 284.13[M+H]+. Anal. Calcd. ForC H NO (283.36): C,
10 7 8 18 21 2
76.29;H,7.47;N,4.94. Found: C,76.25;H,7.49;N,4.92.
(Z)-3-Caren-5-oneO-(4-methylbenzoyl)oxime((Z)-4j). Whitesolid. Yield: 75.3%,m.p.: 125.9–127.6◦C.
UV-Vis(EtOH)λ (logε): 259.30(4.38)nm;IR(KBr,cm−1): 3066(w),3033(w,Ar-H,=C-H),1742
max
(s,C=O),1656(m,C=N),1617(m),1572(m),1510(m),1450(m,Ar);1H-NMRδ=7.99(d,J=8.2Hz,
2H,C -H,C -H),7.27(d,J=6.5Hz,2H,C -H,C -H),6.16(s,1H,C -H),2.55(dd,J=20.2,7.7Hz,
13 17 14 16 4
1H,C -H ),2.42(s,3H,C -CH ),2.21(d,J=20.3Hz,1H,C -H ),2.04(d,J=8.2Hz,1H,C -H),1.84
2 a 15 3 2 b 6
Molecules2017,22,1538 9of15
(s,3H,C -CH ),1.32(t,J=8.0Hz,1H,C -H),1.29(s,3H,C -CH ),0.94(s,3H,C -CH ). 13C-NMR
3 3 1 7 3 7 3
δ=164.23(C ),161.72(C ),147.80(C ),143.75(C ),129.57(C ),129.21(C andC ),126.78(C
11 5 3 15 12 13 17 14
andC ),118.44(C ),28.07(C ),27.15(C ),23.76(C ),23.05(C ),21.70(C ),21.63(C ),21.32(C ),
16 4 6 9 2 1 18 10 7
14.59(C );ESI-MSm/z: 284.17[M+H]+. Anal. Calcd. ForC H NO (283.36): C,76.29;H,7.47;N,
8 18 21 2
4.94. Found: C,76.32;H,7.45;N,4.93.
(Z)-3-Caren-5-oneO-(2,4-dichlorobenzoyl)oxime((Z)-4k). Whitesolid. Yield: 65.0%,m.p.: 82.0–83.0◦C.
UV-Vis(EtOH)λ (logε): 249.50(4.30)nm;IR(KBr,cm−1): 3087(w),3018(w,Ar-H,=C-H),1736(s,
max
C=O),1653(m,C=N),1587(m),1545(m),1468(m),1450(m,Ar);1H-NMRδ=7.85(d,J=8.4Hz,1H,
C -H),7.50(d,J=2.0Hz,1H,C -H),7.34(dd,J=8.4,2.0Hz,1H,C ),6.13(s,1H,C -H),2.55(dd,
17 14 16 4
J=20.6,8.7Hz,1H,C -H ),2.21(d,J=20.3Hz,1H,C -H ),2.05(d,J=8.1Hz,1H,C -H),1.85(s,3H,
2 a 2 b 6
C -CH ),1.30(t,J=8.0Hz,1H,C -H),1.22(s,3H,C -CH ),0.93(s,3H,C -CH ). 13C-NMRδ=163.20
3 3 1 7 3 7 3
(C ),162.44(C ),148.59(C ),138.35(C ),134.38(C ),132.79(C ),130.86( ),128.34( ),127.16
11 5 3 15 13 12 17 14
(C ),118.10(C ),28.10(C ),27.20(C ),23.78(C ),23.16(C ),22.04(C ),21.48(C ),14.56(C );ESI-MS
16 4 6 9 2 1 10 7 8
m/z: 338.06[M+H]+. Anal. Calcd. ForC H Cl NO (338.23): C,60.37;H,5.07;N,4.14. Found: C,
17 17 2 2
60.30;H,5.11;N,4.17.
(Z)-3-Caren-5-oneO-(2,3-dichlorobenzoyl)oxime((Z)-4l). Yellowliquid. Yield: 60.7%. UV-Vis(EtOH)
λ (logε): 254.19(4.16)nm,224.42(4.28)nm;IR(thinfilm,cm−1): 3076(w),3014(w,Ar-H,=C-H),
max
1750(s,C=O),1653(m,C=N),1581(m),1560(w),1516(w),1447(m,Ar);1H-NMRδ=7.71(dd,J=7.8,
1.6Hz, 1H,C -H),7.62(dd, J =8.0, 1.6Hz, 1H,C -H),7.30(t, J =7.9Hz, 1H,C -H),6.13(s, 1H,
17 15 16
C -H),2.55(dd,J=21.1,8.3Hz,1H,C -H ),2.21(d,J=21.1Hz,1H,C -H ),2.02(d,J=8.1Hz,1H,
4 2 a 2 b
C -H),1.85(s,3H,C -CH ),1.30(t,J=8.0Hz,1H,C -H),1.22(s,3H,C -CH ),0.94(s,3H,C -CH ).
6 3 3 1 7 3 7 3
13C-NMRδ=164.70(C ),163.64(C ),149.74(C ),135.48(C ),134.17(C ),133.69(C ),132.38(C ),
11 5 3 12 15 14 13
130.37(C ),128.32(C ),119.05(C ),29.11(C ),28.21(C ),24.78(C ),24.20(C ),23.08( ),22.36(C ),
17 16 4 6 9 2 1 10 7
15.56( );ESI-MSm/z: 337.99[M−H]-. Anal. Calcd. ForC H Cl NO (338.23): C,60.37;H,5.07;N,
8 17 17 2 2
4.14. Found: C,60.40;H,5.09;N,4.15.
(Z)-3-Caren-5-oneO-(4-chloromethylbenzoyl)oxime((Z)-4m).Whitesolid.Yield:78%,m.p.:121.9–123.2◦C.
UV-Vis(EtOH)λ (logε): 258.00(4.23)nm,238.50(4.31)nm;IR(KBr,cm−1): 3039(w),3009(w,Ar-H,
max
=C-H),1748(s,C=O),1653(m,C=N),1611(m),1575(m),1516(w),1426(m,Ar);1H-NMRδ=8.09
(d,J=8.3Hz,2H,C -H,C -H),7.50(d,J=8.2Hz,2H,C -H,C -H),6.16(s,1H,C -H),4.63(s,2H,
13 17 14 16 4
C -H),2.56(dd,J=20.3,8.3Hz,1H,C -H ),2.22(d,J=20.3Hz,1H,C -H ),2.03(d,J=8.1Hz,1H,
18 2 a 2 b
C -H),1.85(s,3H,C -CH ),1.34(t,J=8.2Hz,1H,C -H),1.30(s,3H,C -CH ),0.94(s,3H,C -CH );
6 3 3 1 7 3 7 3
13C-NMRδ=163.66(C ),162.08(C ),148.22(C ),142.39(C ),130.63(C ),129.97(C ,C ),128.62
11 5 3 15 12 13 17
(C ,C ),118.27(C ),45.36(C ),28.10(C ),27.16(C ),23.78(C ),23.12(C ),21.75(C ),21.34(C ),
14 16 4 18 6 9 2 1 10 7
14.59(C );ESI-MSm/z: 318.10[M+H]+. Anal. Calcd. ForC H ClNO (317.81): C,68.03;H,6.34;N,
8 18 20 2
4.41. Found: C,68.00;H,6.35;N,4.43.
(Z)-3-Caren-5-oneO-cyclopentylcarbonyloxime((Z)-4n). Whitesolid. Yield: 64.5%,m.p.: 58.0–60.2◦C.
UV-Vis(EtOH)λ (logε): 241.40(4.19)nm; IR(KBr, cm−1): 3030(w, =C-H),1757(s, C=O),1653
max
(m,C=N);1H-NMRδ=6.07(s,1H,C -H),2.89(p,J=8.0Hz,1H,C -H),2.51(dd,J=20.3,8.4Hz,1H,
4 12
C -H ),2.17(d,J=20.3Hz,1H,C -H ),1.94(tt,J=12.5,6.8Hz,4H,C -H ,C -H ),1.89(d,J=8.2Hz,
2 a 2 b 13 2 16 2
1H,C -H),1.81(s,3H,C -CH ),1.78–1.72(m,2H,C -2H),1.62(dt,J=8.9,4.2Hz,2H,C -H),1.27
6 3 3 14 15
(t,J=8.3Hz,1H,C -H),1.23(s,3H,C -CH ),0.89(s,3H,C -CH ). 13C-NMRδ=174.14(C ),161.27
1 7 3 7 3 11
(C ),147.49(C ),118.48(C ),42.99(C ),30.08(C ),30.02(C ),28.02(C ),27.12(C ),25.86(C and
5 3 4 12 13 16 6 9 14
C ), 23.71 (C ), 22.97 (C ), 21.50 (C ), 21.04 (C ), 14.56 (C ); ESI-MS m/z: 262.13 [M + H]+. Anal.
15 2 1 10 7 8
Calcd. ForC H NO (261.36): C,73.53;H,8.87;N,5.36. Found: C,73.51;H,8.89;N,5.37.
16 23 2
(Z)-3-Caren-5-oneO-cyclohexylcarbonyloxime((Z)-4o). Whitesolid. Yield: 64.8%, m.p.: 81.4–82.5 ◦C.
UV-Vis(EtOH)λ (logε): 243.60(4.29)nm: IR(KBr,cm−1): 3027(w,=C-H),1753(s,C=O),1650(m,
max
C=N);1H-NMRδ=6.07(s,1H,C -H),2.54–2.44(m,2H,C -H ,C -H),2.17(d,J=20.3Hz,1H,C -H ),
4 2 a 12 2 b
1.98(s,2H,C -H),1.89(d,J=8.2Hz,1H,C -H),1.81(s,3H,C -CH ),1.78(dd,J=9.1,3.9Hz,2H,
13 6 3 3
Molecules2017,22,1538 10of15
C -H),1.57(q,J=11.7Hz,2H,C -H),1.37–1.25(m,5H,C -H,C -H,C -H),1.23(s,3H,C -CH ),
17 15 1 14 16 7 3
0.89(s,3H,C -CH );13C-NMRδ=173.30(C ),161.43(C ),147.52(C ),118.47(C ),42.54(C ),29.10
7 3 11 5 3 4 12
(C ),29.03(C ),28.03(C ),27.11(C ),25.77(C ),25.48(C ),25.43(C ),23.70(C ),22.97(C ),21.50
13 17 6 9 14 15 16 2 1
(C ),21.04(C ),14.55(C );ESI-MSm/z: 276.22[M+H]+. Anal. Calcd. ForC H NO (275.39): C,
10 7 8 17 25 2
74.14;H,9.15;N,5.09. Found: C,74.16;H,9.12;N,5.06.
(Z)-3-caren-5-one O-α-furylcarbonyl oxime ((Z)-4p). White solid. Yield: 82.0%, m.p.: 114.7–115.6 ◦C.
UV-Vis(EtOH)λ (logε): 268.90(4.28)nm;IR(KBr,cm−1): 3110(m),3006(w,=C-H),1754(s,C=O),
max
1653(m,C=N);1H-NMRδ=7.65–7.61(m,1H,C -H),7.22(d,J=3.5Hz,1H,C -H),6.55(dd,J=3.5,
15 13
1.7Hz,1H,C -H),6.13(s,1H,C -H),2.55(dd,J=20.3,8.3Hz,1H,C -H ),2.21(d,J=20.3Hz,1H,
14 4 2 a
C -H ),2.02(d,J=8.1Hz,1H,C -H),1.84(s,3H,C -CH ),1.33(t,J=8.1Hz,1H,C -H),1.28(s,4H,
2 b 6 3 3 1
C -CH ),0.93(s,3H,C -CH ). 13C-NMRδ=162.13(C ),156.70(C ),148.25(C ),146.63(C ),143.61
7 3 7 3 11 5 3 12
(C ),118.14(C ),117.95(C ),111.84(C ),28.00(C ),27.19(C ),23.77(C ),23.15(C ),21.78(C ),
15 4 13 14 6 9 2 1 10
21.22(C ),14.54(C );ESI-MSm/z: 260.07[M+H]+. Anal. Calcd. ForC H NO (259.30): C,69.48;H,
7 8 15 17 3
6.61;N,5.40. Found: C,69.50;H,6.58;N,5.41.
(Z)-3-Caren-5-oneO-α-thienylcarbonyloxime((Z)-4q). Whitesolid. Yield: 75.5%,m.p.: 108.4–109.3◦C.
UV-Vis(EtOH)λ (logε):278.80(4.30)nm,253.90(4.36)nm;IR(KBr,cm−1):3116(w),3018(w,=C-H),
max
1739 (s, C=O), 1650 (m, C=N); 1H-NMR δ = 7.91 (dd, J = 3.8, 1.2 Hz, 1H, C -H), 7.59 (dd, J = 5.0,
13
1.2Hz,1H,C -H),7.15(dd,J=4.9,3.8Hz,1H,C -H),6.14(s,1H,C -H),2.55(dd,J=20.6,8.7Hz,
15 14 4
1H,C -H ),2.21(d,J=21.1Hz,1H,C -H ),2.03(d,J=8.1Hz,1H,C -H),1.85(s,3H,C -CH ),1.33
2 a 2 b 6 3 3
(d,J=8.1Hz,1H,C -H),1.31(s,3H,C -CH ),0.93(s,3H,C -CH ). 13C-NMRδ=161.82(C ),159.90
6 7 3 7 3 11
(C ),148.19(C ),133.81(C ),132.45(C ),132.18(C ),127.84(C ),118.15(C ),28.00(C ),27.16(C ),
5 3 12 13 15 14 4 6 9
23.78(C ),23.03(C ),21.70(C ),21.29(C ),14.57(C );ESI-MSm/z: 276.06[M+H]+. Anal. Calcd. For
2 1 10 7 8
C H NO S(275.37): C,65.43;H,6.22;N,5.09. Found: C,65.45;H,6.21;N,5.10.
15 17 2
(Z)-3-Caren-5-one O-β-pyridylcarbonyl oxime ((Z)-4r). Brown solid. Yield: 80.0%, m.p.: 97.0–98.7 ◦C.
UV-Vis(EtOH)λ (logε):262.60(4.18)nm,223.80(4.14)nm;IR(KBr,cm−1):3065(w),3039(w,=C-H),
max
1743(s,C=O),1655(m,C=N);1H-NMRδ=9.28(s,1H,C -H),8.81(d,J=4.8Hz,1H,C -H),8.38(d,
13 14
J=7.9Hz,1H,C -H),7.45(dd,J=7.9,4.9Hz,1H,C -H),6.16(s,1H,C -H),2.57(dd,J=20.3,8.4Hz,
16 15 4
1H,C -H ),2.23(d,J=20.3Hz,1H,C -H ),2.03(d,J=8.1Hz,1H,C -H),1.86(s,3H,C -CH ),1.36
2 a 2 b 6 3 3
(t,J=8.3Hz,1H,C -H),1.31(s,3H,C -CH ),0.95(s,3H,C -CH ). 13C-NMRδ=162.88(C ),162.48
1 7 3 7 3 11
(C ),153.47(C ),150.53(C ),148.73(C ),137.20(C ),125.72(C ),123.55(C ),118.06(C ),28.15
5 3 14 13 16 12 15 4
(C ),27.18(C ),23.81(C ),23.21(C ),21.94(C ),21.34(C ),14.58(C );ESI-MSm/z: 271.14[M+H]+.
6 9 2 6 10 7 8
Anal. Calcd. ForC H N O (270.33): C,71.09;H,6.71;N,10.36. Found: C,71.06;H,6.70;N,10.38.
16 18 2 2
(Z)-3-Caren-5-one O-(2-chloropyridylcarbonyl) oxime ((Z)-4s). Brown solid. Yield: 82.4%, m.p.:
107.1–109.4 ◦C. UV-Vis (EtOH) λ (log ε): 257.50 (4.28) nm, 229.10 (4.15) nm; IR (KBr, cm−1):
max
3051(w), 3018(w,=C-H),1736(s,C=O),1650(m,C=N);1H-NMRδ=8.55(dd,J =4.8, 2.0Hz,1H,
C -H),8.23(dd,J=7.7,2.0Hz,1H,C -H),7.38(dd,J=7.7,4.8Hz,1H,C -H),6.13(s,1H,C -H),2.56
14 16 15 4
(dd,J=20.7,8.7Hz,1H,C -H ),2.22(d,J=21.1Hz,1H,C -H ),2.08(d,J=8.1Hz,1H,C -H),1.86
2 a 2 b 6
(s,3H,C -CH ),1.32(t,J=8.0Hz,1H,C -H),1.24(s,3H,C -CH ),0.94(s,3H,C -CH ). 13C-NMR
3 3 1 7 3 7 3
δ=163.05(C ),162.81(C ),151.91(C ),149.48(C ),149.00(C ),140.74(C ),126.97(C ),122.24
11 5 3 14 13 16 12
(C ),117.92(C ),28.11(C ),27.23(C ),23.80(C ),23.23(C ),22.20(C ),21.46(C ),14.56(C );ESI-MS
15 4 6 9 2 6 10 7 8
m/z: 305.03[M+H]+. Anal. Calcd. ForC H ClN O (304.77): C,63.05;H,5.62;N,9.19. Found: C,
16 17 2 2
63.01;H,5.63;N,9.21.
(Z)-3-Caren-5-oneO-n-hexanoyloxime((Z)-4t). Yellowliquid. Yield: 63.5%. UV-vis(EtOH)λ (logε):
max
241.80(4.23)nm;IR(thinfilm,cm−1): 1766(s,C=O),1659(m,C=N),763(m),751(m,-(CH ) -,n>4);
2 n
1H-NMRδ=6.06(s,1H,C -H),2.51(dd,J=20.3,8.3Hz,1H,C -H ),2.45(t,J=7.5Hz,2H,C -H),2.18
4 2 a 12
(d,J=20.3Hz,1H,C -H ),1.90(d,J=8.2Hz,1H,C -H),1.82(s,3H,C -CH ),1.72(q,J=7.4Hz,2H,
2 b 6 4 3
C -H),1.36(dt,J=7.1,4.4Hz,4H,C -H,C -H),1.28(d,J=8.6Hz,1H,C -H),1.23(s,3H,C -CH ),
13 14 15 1 7 3
0.91(d,J =7.1Hz,3H,C -H),0.89(s,3H,C -CH ). 13C-NMRδ=171.52(C ),161.20(C ),147.60
16 7 3 11 5