Synthesis of bis(1,2,3-triazole) functionalized quinoline-2,4-diones

molecules A icle Syn hesis o Bis(1,2,3-T iazole) Func ionalized Quinoline-2,4-Diones † Da id Mili´ce i´c 1, Roman Kimmel 1, Ma in Gaz oda 2, Damijana U anka 2, S anisla Ka ka 1,* and Janez Košm lj 2,* 1 Depa men o Chemis y, Facul y o Technology, Tomas Ba a Uni e si y in Zlin, 760 01 Zlin, Czech Republic; [email p o ec ed] (D.M.); [email p o ec ed] (R.K.) 2Facul y o Chemis y and Chemical Technology, Uni e si y o Ljubljana, SI-1000 Ljubljana, Slo enia; [email p o ec ed] (M.G.); [email p o ec ed] (D.U.) *Co espondence: [email p o ec ed] (S.K.); [email p o ec ed] (J.K.); Tel.: +420-57-603-1115 (S.K.); +386-1-479-8558 (J.K.) † Dedica ed o P o esso Oldˇ ich Pale a on his 80 h bi hday. Recei ed: 25 June 2018; Accep ed: 4 Sep embe 2018; Published: 10 Sep embe 2018   Abs ac : De i a i es o 3-(1H-1,2,3- iazol-1-yl)quinoline-2,4(1H,3H)-dione unsubs i u ed on quinolone ni ogen a om, which a e a ailable by he p e iously desc ibed ou s ep syn hesis s a ing om aniline, we e exploi ed as in e media es in ob aining he i le compounds. The p ocedu e in ol es he in oduc ion o p opa gyl g oup on o he quinolone ni ogen a om o men ioned in e media es by he eac ion o hem wi h p opa gyl b omide in N,N-dime hyl o mamide (DMF) in p esence o a po assium ca bona e and he subsequen o ma ion o a second iazole ing by coppe ca alyzed cyclisa ion eac ion wi h azido compounds. The p oduc s we e cha ac e ized by 1 H, 13 C and 15 N NMR spec oscopy. The co esponding esonances we e assigned on he basis o he s anda d 1D and g adien selec ed 2D NMR expe imen s ( 1 H– 1 H gs-COSY, 1 H– 13 C gs-HSQC, 1 H– 13 C gs-HMBC) wi h 1 H– 15 N gs-HMBC as a p ac ical ool o de e mine 15 N NMR chemical shi s a he na u al abundance le el o 15N iso ope. Keywo ds: click chemis y; azido g oup; quinoline-2,4(1H,3H)-diones; p opa gyl g oup; bis(1,2,3- iazole) 1. In oduc ion The 1,4-disubs i u ed-1,2,3- iazole he e ocyclic mo i has become an exceedingly popula s uc u e inding applica ions in a b oad ange o a eas including ma e ials, bioma e ials, me allopha maceu icals, sup amolecula chemis y, chemical sensing and ca alysis, o name jus a ew [ 1 ]. In coo dina ion and o ganome allic chemis y, o example, i became an impo an ligand sca old, no only because o simplici y and eliabili y in i s p epa a ion, bu also due o a a ie y o coo dina ion modes o e ing [ 2 – 6 ]. Owing o he disco e y o coppe (I)-ca alyzed 1,3-cycloaddi ion o e minal alkynes wi h o ganic azides, he CuAAC click eac ion, he p epa a ion o 1,4-disubs i u ed-1,2,3- iazole is acili a ed in mild and modula ashion [ 7 , 8 ]. Al hough his “click iazole” has become a pa o a b oad ange o molecules, i s associa ion wi h quinoline-2,4-diones emains la gely unde de eloped. Apa om ou ecen publica ion on 3-(1H-1,2,3- iazol-1-yl)quinoline-2,4(1H,3H)-dione de i a i es ( 1 , Figu e 1) [ 9 ], o he bes o ou knowledge, o he 1,2,3- iazole unc ionalized quinoline-2,4-diones a e unp eceden ed. As pa o ou endea o in quinoline-2,4-dione chemis y [ 10 ] as well as unc ional click iazoles [ 11 , 12 ] and hei applica ions [ 13 ], we became in e es ed in he syn hesis o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 ha may po en ially se e as unc ional sca olds in coo dina ion Molecules 2018,23, 2310; doi:10.3390/molecules23092310 www.mdpi.com/jou nal/molecules Molecules 2018,23, 2310 2 o 21 chemis y, molecula sensing and biochemis y. I is no ewo hy ha many compounds wi h he quinoline-2,4-dione s uc u e we e isola ed om ungi, bac e ia and plan s, possessing b oad ange o in e es ing biological ac i i ies in i o and in i o [ 10 ]. He ein we epo an app oach o quinoline-2,4-diones unsymme ically subs i u ed wi h wo click iazoles, an ex ensi e 1 H, 13 C, and 15 N NMR spec al analyses, and a p elimina y in es iga ion o hei chela ing p ope ies owa ds a ene- u henium. Molecules 2018, 23, x FOR PEER REVIEW 2 o 21 compounds wi h he quinoline-2,4-dione s uc u e we e isola ed om ungi, bac e ia and plan s, possessing b oad ange o in e es ing biological ac i i ies in i o and in i o [10]. He ein we epo an app oach o quinoline-2,4-diones unsymme ically subs i u ed wi h wo click iazoles, an ex ensi e 1H, 13C, and 15N NMR spec al analyses, and a p elimina y in es iga ion o hei chela ing p ope ies owa ds a ene- u henium. N H O O N R 1 N NR 2 N O O N R 1 N NR 2 NN NR 3 12 Figu e 1. A gene al s uc u e o 1,2,3- iazole quinoline-2,4-diones 1 (le ) and he bis(1,2,3- iazole) coun e pa s 2 ( igh ). 2. Resul s and Discussion We easoned ha he desi ed bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 could be ob ained ia p e iously desc ibed 3-(1H-1,2,3- iazol-1-yl)quinoline-2,4(1H,3H)-dione de i a i es 1 as syn he ic in e media es (Scheme 1). The la e we e p epa ed in a ou -s ep eac ion sequence s a ing om aniline, which upon ea men wi h die hyl 2-me hylmalona e and die hyl 2-phenylmalona e ini ially a o ded he co esponding 4-hyd oxyquinolin-2(1H)-ones 3a and 3b [14]. Chlo ina ion wi h sul u yl chlo ide in o 3-me hyl- and 3-phenyl-3-chlo oquinolin-2,4(1H,3H)-diones 4a [15] and 4b [16], ollowed by he nucleophilic displacemen o he chlo ine a oms wi h sodium azide, ga e 3-me hyl- and 3-phenyl- subs i u ed 3-azidoquinoline-2,4(1H,3H)-diones 5a and 5b [16]. Then we began wi h coppe -ca alyzed azide-alkyne cycloaddi ion eac ion (CuAAC). Scheme 1. P epa a ion o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2. Al hough a la ge a ie y o eac ion condi ions ha e been de eloped o he CuAAC eac ion [17,18], ou p e ious wo k in his ield has shown ha o 3-azidoquinoline-2,4(1H,3H)-diones a combina ion o coppe (II) sul a e pen ahyd a e and elemen al coppe (CuSO4/Cu0) in dime hyl sul oxide (DMSO) p o ided esul s ha we e supe io o o he combina ions. Adop ing hose p e ious esul s in his wo k some addi ional op imiza ions o he eac ion condi ions we e ca ied ou wi h 5a and phenylace ylene (6a) as he model subs a es. Sc eening h ough he eac ion sol en s indica ed ha N,N-dime hyl o mamide (DMF) is e en mo e e icien han DMSO, p o iding he desi ed a ge compound 1a in sho e eac ion imes. The in luence o he amoun o g anula coppe o he cou se o he eac ion be ween 5a and equimola amoun o 6a in DMF was also b ie ly in es iga ed. While keeping he loading o CuSO4·5H2O cons an a 10 mol % ela i e o 5a, he amoun o he elemen al coppe was a ied om 380 mol % o 100 mol %. The esul s a e summa ized in Table 1. Figu e 1. A gene al s uc u e o 1,2,3- iazole quinoline-2,4-diones 1 ( le ) and he bis(1,2,3- iazole) coun e pa s 2( igh ). 2. Resul s and Discussion We easoned ha he desi ed bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 could be ob ained ia p e iously desc ibed 3-(1H-1,2,3- iazol-1-yl)quinoline-2,4(1H,3H)-dione de i a i es 1 as syn he ic in e media es (Scheme 1). The la e we e p epa ed in a ou -s ep eac ion sequence s a ing om aniline, which upon ea men wi h die hyl 2-me hylmalona e and die hyl 2-phenylmalona e ini ially a o ded he co esponding 4-hyd oxyquinolin-2(1H)-ones 3a and 3b [ 14 ]. Chlo ina ion wi h sul u yl chlo ide in o 3-me hyl- and 3-phenyl-3-chlo oquinolin-2,4(1H,3H)-diones 4a [ 15 ] and 4b [ 16 ], ollowed by he nucleophilic displacemen o he chlo ine a oms wi h sodium azide, ga e 3-me hyl- and 3-phenyl- subs i u ed 3-azidoquinoline-2,4(1H,3H)-diones 5a and 5b [ 16 ]. Then we began wi h coppe -ca alyzed azide-alkyne cycloaddi ion eac ion (CuAAC). Molecules 2018, 23, x FOR PEER REVIEW 2 o 21 compounds wi h he quinoline-2,4-dione s uc u e we e isola ed om ungi, bac e ia and plan s, possessing b oad ange o in e es ing biological ac i i ies in i o and in i o [10]. He ein we epo an app oach o quinoline-2,4-diones unsymme ically subs i u ed wi h wo click iazoles, an ex ensi e 1H, 13C, and 15N NMR spec al analyses, and a p elimina y in es iga ion o hei chela ing p ope ies owa ds a ene- u henium. N H O O N R 1 N NR 2 N O O N R 1 N NR 2 NN NR 3 12 Figu e 1. A gene al s uc u e o 1,2,3- iazole quinoline-2,4-diones 1 (le ) and he bis(1,2,3- iazole) coun e pa s 2 ( igh ). 2. Resul s and Discussion We easoned ha he desi ed bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 could be ob ained ia p e iously desc ibed 3-(1H-1,2,3- iazol-1-yl)quinoline-2,4(1H,3H)-dione de i a i es 1 as syn he ic in e media es (Scheme 1). The la e we e p epa ed in a ou -s ep eac ion sequence s a ing om aniline, which upon ea men wi h die hyl 2-me hylmalona e and die hyl 2-phenylmalona e ini ially a o ded he co esponding 4-hyd oxyquinolin-2(1H)-ones 3a and 3b [14]. Chlo ina ion wi h sul u yl chlo ide in o 3-me hyl- and 3-phenyl-3-chlo oquinolin-2,4(1H,3H)-diones 4a [15] and 4b [16], ollowed by he nucleophilic displacemen o he chlo ine a oms wi h sodium azide, ga e 3-me hyl- and 3-phenyl- subs i u ed 3-azidoquinoline-2,4(1H,3H)-diones 5a and 5b [16]. Then we began wi h coppe -ca alyzed azide-alkyne cycloaddi ion eac ion (CuAAC). Scheme 1. P epa a ion o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2. Al hough a la ge a ie y o eac ion condi ions ha e been de eloped o he CuAAC eac ion [17,18], ou p e ious wo k in his ield has shown ha o 3-azidoquinoline-2,4(1H,3H)-diones a combina ion o coppe (II) sul a e pen ahyd a e and elemen al coppe (CuSO4/Cu0) in dime hyl sul oxide (DMSO) p o ided esul s ha we e supe io o o he combina ions. Adop ing hose p e ious esul s in his wo k some addi ional op imiza ions o he eac ion condi ions we e ca ied ou wi h 5a and phenylace ylene (6a) as he model subs a es. Sc eening h ough he eac ion sol en s indica ed ha N,N-dime hyl o mamide (DMF) is e en mo e e icien han DMSO, p o iding he desi ed a ge compound 1a in sho e eac ion imes. The in luence o he amoun o g anula coppe o he cou se o he eac ion be ween 5a and equimola amoun o 6a in DMF was also b ie ly in es iga ed. While keeping he loading o CuSO4·5H2O cons an a 10 mol % ela i e o 5a, he amoun o he elemen al coppe was a ied om 380 mol % o 100 mol %. The esul s a e summa ized in Table 1. Scheme 1. P epa a ion o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2. Al hough a la ge a ie y o eac ion condi ions ha e been de eloped o he CuAAC eac ion [ 17 , 18 ], ou p e ious wo k in his ield has shown ha o 3-azidoquinoline-2,4(1H,3H)-diones a combina ion o coppe (II) sul a e pen ahyd a e and elemen al coppe (CuSO 4 /Cu 0 ) in dime hyl sul oxide (DMSO) p o ided esul s ha we e supe io o o he combina ions. Adop ing hose p e ious esul s in his wo k some addi ional op imiza ions o he eac ion condi ions we e ca ied ou wi h 5a and phenylace ylene ( 6a ) as he model subs a es. Sc eening h ough he eac ion sol en s indica ed ha N,N-dime hyl o mamide (DMF) is e en mo e e icien han DMSO, p o iding he desi ed a ge compound 1a in sho e eac ion imes. The in luence o he amoun o g anula coppe o he cou se o he eac ion be ween 5a and equimola amoun o 6a in DMF was also b ie ly in es iga ed. While keeping he loading o CuSO 4· 5H 2 O cons an a 10 mol % ela i e o 5a , he amoun o he elemen al coppe was a ied om 380 mol % o 100 mol %. The esul s a e summa ized in Table 1. Molecules 2018,23, 2310 3 o 21 Table 1. The E ec o G anula Coppe o he Con e sion o 5a in o 1a a. Molecules 2018, 23, x FOR PEER REVIEW 3 o 21 Table 1. The E ec o G anula Coppe o he Con e sion o 5a in o 1a a. Cu, CuSO 4 DMF, Ph 1a5a 6a N H O O Ph N 3 N H O O N Ph N NPh En y Cu0 (mmol) Reac ion Time (h) Yield b (%) 1 3.8 0.75 98 2 3 0.75 91 3 2 1 89 4 1 25 82 c a Reac ion condi ions: 5a (1 mmol), phenylace ylene (1 mmol), and CuSO4·5H2O (0.1 mmol), DMF (4 mL), . The eac ion ime was de e mined by hin-laye ch oma og aphy (TLC) moni o ing o he eac ion mix u e. b Re e s o he yield o isola ed pu e p oduc . c Comple e consump ion o 5a was no eached. Based on he abo e, in a gene al p ocedu e, a mix u e o 3-azidoquinoline-2,4(1H,3H)-dione (5, 1.0 mmol), a sligh excess o e minal alkyne 6 (1.05 mmol), CuSO4⋅5H2O (0.12 mmol), and g anula coppe (2.0 mmol) in DMF (2.3 mL) was s i ed a oom empe a u e, in he p esence o ai . In addi ion o phenylace ylene (6a), p opa gyl alcohol (6b) was selec ed as he ace ylene pa ne . The eac ions we e comple ed wi hin 30 min. As indica ed in Table 2, he p oduc s 1 we e ob ained in excellen yields. By using a mo e s anda d CuSO4·5H2O/L-asco bic acid ca alys in CH2Cl2/wa e biphasic sys em, he cycloaddi ion be ween 5a and 6a equi ed subs an ially longe eac ion ime (48 h) o achie e a simila yield o he p oduc 1a as compa ed o he abo e CuSO4/Cu0/DMF condi ions (En ies 1 and 2). Table 2. P epa a ion o compounds 1. Cu, CuSO 4 DMF, R 2 6 N H O O R 1 N 3 51 N H O O N R 1 N NR 2 En y Azide 5 R1 Ace ylene 6 R2 P oduc 1 Yield a 1 5a Me 6a Ph 1a 95 2 5a Me 6a Ph 1a 83 b 3 5b Ph 6a Ph 1b 86 4 5a Me 6b CH2OH 1c 99 5 5b Ph 6b CH2OH 1d 98 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . b Employing CuSO4·5H2O/L-asco bic acid/CH2Cl2/wa e condi ions, 48 h eac ion ime. P io o he in oduc ion o p opa gyl g oup a he N1 ni ogen a om o he quinoline-2,4(1H,3H)-dione ing in 1, he p ima y hyd oxyl g oups a 1c and 1d we e p o ec ed by ace yla ion by using ace ic anhyd ide in py idine as shown in Scheme 2. The co esponding ace a es 1e and 1 we e ob ained in 84–85% yields. En y Cu0(mmol) Reac ion Time (h) Yield b(%) 1 3.8 0.75 98 2 3 0.75 91 3 2 1 89 4 1 25 82 c a Reac ion condi ions: 5a (1 mmol), phenylace ylene (1 mmol), and CuSO 4· 5H 2 O (0.1 mmol), DMF (4 mL), . The eac ion ime was de e mined by hin-laye ch oma og aphy (TLC) moni o ing o he eac ion mix u e. bRe e s o he yield o isola ed pu e p oduc . cComple e consump ion o 5a was no eached. Based on he abo e, in a gene al p ocedu e, a mix u e o 3-azidoquinoline-2,4(1H,3H)-dione ( 5 , 1.0 mmol), a sligh excess o e minal alkyne 6 (1.05 mmol), CuSO 4· 5H 2 O (0.12 mmol), and g anula coppe (2.0 mmol) in DMF (2.3 mL) was s i ed a oom empe a u e, in he p esence o ai . In addi ion o phenylace ylene ( 6a ), p opa gyl alcohol ( 6b ) was selec ed as he ace ylene pa ne . The eac ions we e comple ed wi hin 30 min. As indica ed in Table 2, he p oduc s 1 we e ob ained in excellen yields. By using a mo e s anda d CuSO 4· 5H 2 O/L-asco bic acid ca alys in CH 2 Cl 2 /wa e biphasic sys em, he cycloaddi ion be ween 5a and 6a equi ed subs an ially longe eac ion ime (48 h) o achie e a simila yield o he p oduc 1a as compa ed o he abo e CuSO4/Cu0/DMF condi ions (En ies 1 and 2). Table 2. P epa a ion o compounds 1. Molecules 2018, 23, x FOR PEER REVIEW 3 o 21 Table 1. The E ec o G anula Coppe o he Con e sion o 5a in o 1a a. Cu, CuSO 4 DMF, Ph 1a5a 6a N H O O Ph N 3 N H O O N Ph N NPh En y Cu0 (mmol) Reac ion Time (h) Yield b (%) 1 3.8 0.75 98 2 3 0.75 91 3 2 1 89 4 1 25 82 c a Reac ion condi ions: 5a (1 mmol), phenylace ylene (1 mmol), and CuSO4·5H2O (0.1 mmol), DMF (4 mL), . The eac ion ime was de e mined by hin-laye ch oma og aphy (TLC) moni o ing o he eac ion mix u e. b Re e s o he yield o isola ed pu e p oduc . c Comple e consump ion o 5a was no eached. Based on he abo e, in a gene al p ocedu e, a mix u e o 3-azidoquinoline-2,4(1H,3H)-dione (5, 1.0 mmol), a sligh excess o e minal alkyne 6 (1.05 mmol), CuSO4⋅5H2O (0.12 mmol), and g anula coppe (2.0 mmol) in DMF (2.3 mL) was s i ed a oom empe a u e, in he p esence o ai . In addi ion o phenylace ylene (6a), p opa gyl alcohol (6b) was selec ed as he ace ylene pa ne . The eac ions we e comple ed wi hin 30 min. As indica ed in Table 2, he p oduc s 1 we e ob ained in excellen yields. By using a mo e s anda d CuSO4·5H2O/L-asco bic acid ca alys in CH2Cl2/wa e biphasic sys em, he cycloaddi ion be ween 5a and 6a equi ed subs an ially longe eac ion ime (48 h) o achie e a simila yield o he p oduc 1a as compa ed o he abo e CuSO4/Cu0/DMF condi ions (En ies 1 and 2). Table 2. P epa a ion o compounds 1. Cu, CuSO 4 DMF, R 2 6 N H O O R 1 N 3 51 N H O O N R 1 N NR 2 En y Azide 5 R1 Ace ylene 6 R2 P oduc 1 Yield a 1 5a Me 6a Ph 1a 95 2 5a Me 6a Ph 1a 83 b 3 5b Ph 6a Ph 1b 86 4 5a Me 6b CH2OH 1c 99 5 5b Ph 6b CH2OH 1d 98 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . b Employing CuSO4·5H2O/L-asco bic acid/CH2Cl2/wa e condi ions, 48 h eac ion ime. P io o he in oduc ion o p opa gyl g oup a he N1 ni ogen a om o he quinoline-2,4(1H,3H)-dione ing in 1, he p ima y hyd oxyl g oups a 1c and 1d we e p o ec ed by ace yla ion by using ace ic anhyd ide in py idine as shown in Scheme 2. The co esponding ace a es 1e and 1 we e ob ained in 84–85% yields. En y Azide 5 R1Ace ylene 6 R2P oduc 1 Yield a 15a Me 6a Ph 1a 95 25a Me 6a Ph 1a 83 b 35b Ph 6a Ph 1b 86 45a Me 6b CH2OH 1c 99 55b Ph 6b CH2OH 1d 98 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . b Employing CuSO 4· 5H 2 O/L-asco bic acid/CH2Cl2/wa e condi ions, 48 h eac ion ime. P io o he in oduc ion o p opa gyl g oup a he N1 ni ogen a om o he quinoline-2,4(1H,3H)-dione ing in 1 , he p ima y hyd oxyl g oups a 1c and 1d we e p o ec ed by ace yla ion by using ace ic anhyd ide in py idine as shown in Scheme 2. The co esponding ace a es 1e and 1 we e ob ained in 84–85% yields. Molecules 2018, 23, x FOR PEER REVIEW 4 o 21 1c (R 1 = Me) 1d (R 1 = Ph) N H O O N R 1 N N N H O O N R 1 N N OH OAc 1e (R 1 = Me), 84% 1 (R 1 = Ph), 85% Ac 2 O, Py Scheme 2. P epa a ion o compounds 1e and 1 . Alkyla ion o compounds 1a,b,e, wi h p opa gyl g oup was ca ied ou by using 1.5 equi alen o p opa gyl b omide (6c) and 3 equi alen s o po assium ca bona e in DMF. These eac ions p oceeded smoo hly wi hin 45 min a oom empe a u e. The yields a e gi en in Table 3. Table 3. P epa a ion o compounds 7. B K 2 CO 3 DMF, 6c 7 1 N H O O N R 1 N NR 2 N O O N R 1 N NR 2 En y 1 R1 R 2 6 Yield o 7 (%) a 1 1a Me Ph 6c 7a , 96 2 1b Ph Ph 6c 7b , 79 3 1e Me CH2OAc 6c 7c , 81 4 1 Ph CH2OAc 6c 7d , 63 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . Al hough N-alkyla ion o he lac am g oup usually akes place p e e en ially in quinoline-2,4(1H,3H)-diones [10], he compe i i e O-alkyla ion has been documen ed in simila sys ems [19]. The N1 posi ion o hus in oduced p opa gyl g oup in 7 was con i med by 2D NMR spec oscopy in pa icula by he p esence o he long- ange co ela ions be ween he p opa gyl me hylene p o ons and ca bon a oms C-8a and C-2 in he 1H-13C HMBC spec a (in 7a,c,d) as well as N1 ni ogen a om in he 1H–15N gs-HMBC spec um (in 7a). As he las s ep o he eac ion sequence shown in Scheme 1, mono iazoles 7 we e submi ed o a second cycloaddi ion wi h selec ed azides 8 o gi e he expec ed bis- iazoles 2. Benzyl azide (8a), azidobenzene (8b) and e azolo[1,5-a]py idine (8c) we e selec ed as he eac ion pa ne s. Whe eas benzyl azide (8a) and azidobenzene (8b) eadily eac ed in o he desi ed p oduc s 2a,b,d,e,g,h,j,k a oom empe a u e, e azolo[1,5-a]py idine (8c), a syn he ic equi alen o 2-azidopy idine (8c’), equi ed ha she eac ion condi ions (Table 4). This can be explained by he e azolyl o m in which compound 8c exis s p edominan ly a oom empe a u e [11]. As he p opo ion o he azido isome inc eases a ele a ed empe a u e, he eac ions wi h 8c we e conduc ed a 100 °C, o a o d compounds 2c, ,i,l in good yields. Scheme 2. P epa a ion o compounds 1e and 1 . Molecules 2018,23, 2310 4 o 21 Alkyla ion o compounds 1a , b , e , wi h p opa gyl g oup was ca ied ou by using 1.5 equi alen o p opa gyl b omide ( 6c ) and 3 equi alen s o po assium ca bona e in DMF. These eac ions p oceeded smoo hly wi hin 45 min a oom empe a u e. The yields a e gi en in Table 3. Table 3. P epa a ion o compounds 7. Molecules 2018, 23, x FOR PEER REVIEW 4 o 21 1c (R 1 = Me) 1d (R 1 = Ph) N H O O N R 1 N N N H O O N R 1 N N OH OAc 1e (R 1 = Me), 84% 1 (R 1 = Ph), 85% Ac 2 O, Py Scheme 2. P epa a ion o compounds 1e and 1 . Alkyla ion o compounds 1a,b,e, wi h p opa gyl g oup was ca ied ou by using 1.5 equi alen o p opa gyl b omide (6c) and 3 equi alen s o po assium ca bona e in DMF. These eac ions p oceeded smoo hly wi hin 45 min a oom empe a u e. The yields a e gi en in Table 3. Table 3. P epa a ion o compounds 7. B K 2 CO 3 DMF, 6c 7 1 N H O O N R 1 N NR 2 N O O N R 1 N NR 2 En y 1 R1 R 2 6 Yield o 7 (%) a 1 1a Me Ph 6c 7a , 96 2 1b Ph Ph 6c 7b , 79 3 1e Me CH2OAc 6c 7c , 81 4 1 Ph CH2OAc 6c 7d , 63 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . Al hough N-alkyla ion o he lac am g oup usually akes place p e e en ially in quinoline-2,4(1H,3H)-diones [10], he compe i i e O-alkyla ion has been documen ed in simila sys ems [19]. The N1 posi ion o hus in oduced p opa gyl g oup in 7 was con i med by 2D NMR spec oscopy in pa icula by he p esence o he long- ange co ela ions be ween he p opa gyl me hylene p o ons and ca bon a oms C-8a and C-2 in he 1H-13C HMBC spec a (in 7a,c,d) as well as N1 ni ogen a om in he 1H–15N gs-HMBC spec um (in 7a). As he las s ep o he eac ion sequence shown in Scheme 1, mono iazoles 7 we e submi ed o a second cycloaddi ion wi h selec ed azides 8 o gi e he expec ed bis- iazoles 2. Benzyl azide (8a), azidobenzene (8b) and e azolo[1,5-a]py idine (8c) we e selec ed as he eac ion pa ne s. Whe eas benzyl azide (8a) and azidobenzene (8b) eadily eac ed in o he desi ed p oduc s 2a,b,d,e,g,h,j,k a oom empe a u e, e azolo[1,5-a]py idine (8c), a syn he ic equi alen o 2-azidopy idine (8c’), equi ed ha she eac ion condi ions (Table 4). This can be explained by he e azolyl o m in which compound 8c exis s p edominan ly a oom empe a u e [11]. As he p opo ion o he azido isome inc eases a ele a ed empe a u e, he eac ions wi h 8c we e conduc ed a 100 °C, o a o d compounds 2c, ,i,l in good yields. En y 1 R1R26 Yield o 7 (%) a 11a Me Ph 6c 7a, 96 21b Ph Ph 6c 7b, 79 31e Me CH2OAc 6c 7c, 81 41 Ph CH2OAc 6c 7d, 63 aRe e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . Al hough N-alkyla ion o he lac am g oup usually akes place p e e en ially in quinoline-2,4(1H,3H)-diones [ 10 ], he compe i i e O-alkyla ion has been documen ed in simila sys ems [ 19 ]. The N1 posi ion o hus in oduced p opa gyl g oup in 7 was con i med by 2D NMR spec oscopy in pa icula by he p esence o he long- ange co ela ions be ween he p opa gyl me hylene p o ons and ca bon a oms C-8a and C-2 in he 1 H- 13 C HMBC spec a (in 7a , c , d ) as well as N1 ni ogen a om in he 1H–15Ngs-HMBC spec um (in 7a). As he las s ep o he eac ion sequence shown in Scheme 1, mono iazoles 7 we e submi ed o a second cycloaddi ion wi h selec ed azides 8 o gi e he expec ed bis- iazoles 2 . Benzyl azide ( 8a ), azidobenzene ( 8b ) and e azolo[1,5-a]py idine ( 8c ) we e selec ed as he eac ion pa ne s. Whe eas benzyl azide ( 8a ) and azidobenzene ( 8b ) eadily eac ed in o he desi ed p oduc s 2a , b , d , e , g , h , j , k a oom empe a u e, e azolo[1,5-a]py idine ( 8c ), a syn he ic equi alen o 2-azidopy idine ( 8c’ ), equi ed ha she eac ion condi ions (Table 4). This can be explained by he e azolyl o m in which compound 8c exis s p edominan ly a oom empe a u e [ 11 ]. As he p opo ion o he azido isome inc eases a ele a ed empe a u e, he eac ions wi h 8c we e conduc ed a 100 ◦ C, o a o d compounds 2c, ,i,lin good yields. In his case oo, some s anda d click ca alys /sol en combina ions we e b ie ly e alua ed. The cycloaddi ion be ween ace ylene 7c and benzyl azide ( 8a ) wi h CuSO 4· 5H 2 O/Na-asco ba e (o L-asco bic acid) pai in CH 2 Cl 2 /wa e and -BuOH/wa e sol en sys ems equi ed p olonged eac ion imes, p o iding lowe yields o he p oduc 2d as compa ed o he CuSO 4 /Cu 0 /DMF condi ions (compa e En ies 4–7). In he case o -BuOH/wa e he p esence o wa e in he eac ion mix u e u ned he eac an s and p oduc s in o a gummy ma e ial ha s uck o he eac ion essel and he magne ic s i ing ba , impeding he eac ion om going o comple ion, as al eady no iced o click eac ions wi h highly hyd ophobic eagen s [20]. In p inciple, he “click-p opa gyla ion-click” eac ion sequence a 3-azidoquinoline-2,4-diones 5 could be al e ed, p o iding he a ge bis-(1,2,3- iazole) unc ionalized p oduc s 2 ia bi unc ional azidoe hynyl quinoline-2,4-dione in e media e 9 as shown in Scheme 3. This would allow o hogonal sequen ial syn he ic s a egies o accessing bis(1,2,3- iazole) unc ionalized ma e ials [ 21 ]. We b ie ly explo ed his possibili y by ea ing 3-azido-1-p opa gylquinoline-2,4-dione de i a i e 9a wi h phenylace ylene ( 6a ) o benzyl azide ( 8a ) unde he abo e men ioned CuSO 4 /Cu 0 /DMF condi ions. The co esponding mono iazoles 7a (16%) and 10a (42%), espec i ely, we e ob ained in mode a e yields. Molecules 2018,23, 2310 5 o 21 Table 4. P epa a ion o compounds 2. Molecules 2018, 23, x FOR PEER REVIEW 5 o 21 Table 4. P epa a ion o compounds 2. En y 2 R1 R 2 R 3 (°C) Time (h) Yield a (%) 1 a Me Ph Bn 23 1 97 2 b Me Ph Ph 23 1 99 3 c Me Ph 2-Py 100 0.5 93 4 d Me CH2OAc Bn 23 0.5 96 5 d Me CH2OAc Bn 23 4 85 b 6 d Me CH2OAc Bn 23 48 81 c 7 d Me CH2OAc Bn 23 45 45 d 8 e Me CH2OAc Ph 23 2 92 9 Me CH2OAc 2-Py 100 1 85 10 g Ph Ph Bn 23 1 92 11 h Ph Ph Ph 23 1 94 12 i Ph Ph 2-Py 100 0.75 57 13 j Ph CH2OAc Bn 23 2 97 14 k Ph CH2OAc Ph 23 0.5 93 15 l Ph CH2OAc 2-Py 100 0.5 85 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . b Employing CH2Cl2/wa e /CuSO4·5H2O/Na-asco ba e condi ions. c Employing -BuOH/wa e /CH3CN/CuSO4·5H2O/ Na-asco ba e condi ions. d Employing -BuOH/wa e /CuSO4·5H2O/L-asco bic acid condi ions. In his case oo, some s anda d click ca alys /sol en combina ions we e b ie ly e alua ed. The cycloaddi ion be ween ace ylene 7c and benzyl azide (8a) wi h CuSO4·5H2O/Na-asco ba e (o L-asco bic acid) pai in CH2Cl2/wa e and -BuOH/wa e sol en sys ems equi ed p olonged eac ion imes, p o iding lowe yields o he p oduc 2d as compa ed o he CuSO 4/Cu0/DMF condi ions (compa e En ies 4–7). In he case o -BuOH/wa e he p esence o wa e in he eac ion mix u e u ned he eac an s and p oduc s in o a gummy ma e ial ha s uck o he eac ion essel and he magne ic s i ing ba , impeding he eac ion om going o comple ion, as al eady no iced o click eac ions wi h highly hyd ophobic eagen s [20]. In p inciple, he “click-p opa gyla ion-click” eac ion sequence a 3-azidoquinoline-2,4-diones 5 could be al e ed, p o iding he a ge bis-(1,2,3- iazole) unc ionalized p oduc s 2 ia bi unc ional azidoe hynyl quinoline-2,4-dione in e media e 9 as shown in Scheme 3. This would allow o hogonal sequen ial syn he ic s a egies o accessing bis(1,2,3- iazole) unc ionalized ma e ials [21]. We b ie ly explo ed his possibili y by ea ing 3-azido-1-p opa gylquinoline-2,4-dione de i a i e 9a wi h phenylace ylene (6a) o benzyl azide (8a) unde he abo e men ioned CuSO4/Cu0/DMF condi ions. The co esponding mono iazoles 7a (16%) and 10a (42%), espec i ely, we e ob ained in mode a e yields. En y 2 R1R2R3 (◦C) Time (h) Yield a(%) 1aMe Ph Bn 23 1 97 2bMe Ph Ph 23 1 99 3cMe Ph 2-Py 100 0.5 93 4dMe CH2OAc Bn 23 0.5 96 5dMe CH2OAc Bn 23 4 85 b 6dMe CH2OAc Bn 23 48 81 c 7dMe CH2OAc Bn 23 45 45 d 8eMe CH2OAc Ph 23 2 92 9 Me CH2OAc 2-Py 100 1 85 10 gPh Ph Bn 23 1 92 11 hPh Ph Ph 23 1 94 12 iPh Ph 2-Py 100 0.75 57 13 jPh CH2OAc Bn 23 2 97 14 kPh CH2OAc Ph 23 0.5 93 15 lPh CH2OAc 2-Py 100 0.5 85 a Re e s o pe cen yield o pu e (by TLC and IR) isola ed p oduc . b Employing CH 2 Cl 2 /wa e /CuSO 4· 5H 2 O/ Na-asco ba e condi ions. c Employing -BuOH/wa e /CH 3 CN/CuSO 4· 5H 2 O/Na-asco ba e condi ions. d Employing -BuOH/wa e /CuSO4·5H2O/L-asco bic acid condi ions. Molecules 2018, 23, x FOR PEER REVIEW 6 o 21 Scheme 3. An al e na i e app oach o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 h ough a “p opa gyla ion-click-click” eac ion sequence. The compounds 2a–l we e cha ac e ized by 1H, 13C and, wi h he excep ion o 2a,g,h, also by 15N NMR spec oscopy. The co esponding esonances we e assigned on he basis o g adien -selec ed 2D NMR expe imen s including 1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC and 1H–15N gs-HMBC. Fo he a om numbe ing scheme, see Figu e 2. Some cha ac e is ic spec al ea u es a e discussed below. Figu e 2. Selec ed ing and a om numbe ing along wi h he chemical shi da a (mean alues ounded up o whole numbe s a e p o ided). The 13C and 15N chemical shi s o iazole ings A and D (Tables 5 and 6) a e in a good ag eemen wi h hose epo ed p e iously [11]. To p elimina ily assess he applicabili y o bis- iazole compounds 2 as ligands, we decided o examine hei coo dina ion abili ies o a ene- u henium. NMR expe imen was designed in which compound 2b and equimola amoun o u henium (0.5 equi o [RuCl(μ-Cl)(η6-p-cymene)]2) we e mixed in CDCl3 in NMR ube a oom empe a u e. CDCl3 was selec ed as he eac ion sol en in place o he coo dina i e DMSO-d6 o a oid possible in e e ence wi h he me al cen e (Scheme 4). The eac ion mix u e was moni o ed by ime dependen 1H NMR spec oscopy indica ing an ins an change in he esonances o 2b and p-cymene ligands upon mixing o o m a new se o esonances ha emained unchanged o e se e al days. As shown in Figu es 3 and 4, bo h p o on and ca bon NMR esonances we e se e ely b oadened sugges ing he p esence o a dynamic p ocess in he solu ion, p esumably an equilib ium wi h he s a ing ligand, which can esul om a ela i ely weak ligand- o-me al in e ac ion. Un o una ely, b oad NMR esonances p e en ed an unambiguous s uc u e de e mina ion o he p oduc [Ru–Cym]-2b h ough he 2D NMR echniques due o o e lap as well as lack o se e al indica i e c osspeaks in he spec a, especially in 1H–15N gs-HMBC. Ne e heless, he analysis o he a ailable NMR da a en a i ely sugges ed he coo dina ion o bo h 1,2,3- iazole ings o he Ru–Cym uni as indica ed in Scheme 4. Al hough he coo dina ion p ope ies o he 1,2,3- iazole ni ogen a om N2 a e weak, some o us ha e p e iously shown ha such chela es can be g ea ly s abilized h ough an assis ance o auxilia y ligand [22]. Scheme 3. An al e na i e app oach o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 h ough a “p opa gyla ion-click-click” eac ion sequence. The compounds 2a – l we e cha ac e ized by 1 H, 13 C and, wi h he excep ion o 2a , g , h , also by 15 N NMR spec oscopy. The co esponding esonances we e assigned on he basis o g adien -selec ed 2D NMR expe imen s including 1 H– 1 Hgs-COSY, 1 H– 13 Cgs-HSQC, 1 H– 13 Cgs-HMBC and 1 H– 15 N gs-HMBC. Fo he a om numbe ing scheme, see Figu e 2. Some cha ac e is ic spec al ea u es a e discussed below. Molecules 2018,23, 2310 6 o 21 Molecules 2018, 23, x FOR PEER REVIEW 6 o 21 Scheme 3. An al e na i e app oach o bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones 2 h ough a “p opa gyla ion-click-click” eac ion sequence. The compounds 2a–l we e cha ac e ized by 1H, 13C and, wi h he excep ion o 2a,g,h, also by 15N NMR spec oscopy. The co esponding esonances we e assigned on he basis o g adien -selec ed 2D NMR expe imen s including 1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC and 1H–15N gs-HMBC. Fo he a om numbe ing scheme, see Figu e 2. Some cha ac e is ic spec al ea u es a e discussed below. Figu e 2. Selec ed ing and a om numbe ing along wi h he chemical shi da a (mean alues ounded up o whole numbe s a e p o ided). The 13C and 15N chemical shi s o iazole ings A and D (Tables 5 and 6) a e in a good ag eemen wi h hose epo ed p e iously [11]. To p elimina ily assess he applicabili y o bis- iazole compounds 2 as ligands, we decided o examine hei coo dina ion abili ies o a ene- u henium. NMR expe imen was designed in which compound 2b and equimola amoun o u henium (0.5 equi o [RuCl(μ-Cl)(η6-p-cymene)]2) we e mixed in CDCl3 in NMR ube a oom empe a u e. CDCl3 was selec ed as he eac ion sol en in place o he coo dina i e DMSO-d6 o a oid possible in e e ence wi h he me al cen e (Scheme 4). The eac ion mix u e was moni o ed by ime dependen 1H NMR spec oscopy indica ing an ins an change in he esonances o 2b and p-cymene ligands upon mixing o o m a new se o esonances ha emained unchanged o e se e al days. As shown in Figu es 3 and 4, bo h p o on and ca bon NMR esonances we e se e ely b oadened sugges ing he p esence o a dynamic p ocess in he solu ion, p esumably an equilib ium wi h he s a ing ligand, which can esul om a ela i ely weak ligand- o-me al in e ac ion. Un o una ely, b oad NMR esonances p e en ed an unambiguous s uc u e de e mina ion o he p oduc [Ru–Cym]-2b h ough he 2D NMR echniques due o o e lap as well as lack o se e al indica i e c osspeaks in he spec a, especially in 1H–15N gs-HMBC. Ne e heless, he analysis o he a ailable NMR da a en a i ely sugges ed he coo dina ion o bo h 1,2,3- iazole ings o he Ru–Cym uni as indica ed in Scheme 4. Al hough he coo dina ion p ope ies o he 1,2,3- iazole ni ogen a om N2 a e weak, some o us ha e p e iously shown ha such chela es can be g ea ly s abilized h ough an assis ance o auxilia y ligand [22]. Figu e 2. Selec ed ing and a om numbe ing along wi h he chemical shi da a (mean alues ounded up o whole numbe s a e p o ided). The 13 C and 15 N chemical shi s o iazole ings A and D (Tables 5and 6) a e in a good ag eemen wi h hose epo ed p e iously [11]. To p elimina ily assess he applicabili y o bis- iazole compounds 2 as ligands, we decided o examine hei coo dina ion abili ies o a ene- u henium. NMR expe imen was designed in which compound 2b and equimola amoun o u henium (0.5 equi o [RuCl( µ -Cl)( η6 -p-cymene)] 2 ) we e mixed in CDCl 3 in NMR ube a oom empe a u e. CDCl 3 was selec ed as he eac ion sol en in place o he coo dina i e DMSO-d 6 o a oid possible in e e ence wi h he me al cen e (Scheme 4). The eac ion mix u e was moni o ed by ime dependen 1 H NMR spec oscopy indica ing an ins an change in he esonances o 2b and p-cymene ligands upon mixing o o m a new se o esonances ha emained unchanged o e se e al days. As shown in Figu es 3and 4, bo h p o on and ca bon NMR esonances we e se e ely b oadened sugges ing he p esence o a dynamic p ocess in he solu ion, p esumably an equilib ium wi h he s a ing ligand, which can esul om a ela i ely weak ligand- o-me al in e ac ion. Un o una ely, b oad NMR esonances p e en ed an unambiguous s uc u e de e mina ion o he p oduc [Ru–Cym]- 2b h ough he 2D NMR echniques due o o e lap as well as lack o se e al indica i e c osspeaks in he spec a, especially in 1 H– 15 Ngs-HMBC. Ne e heless, he analysis o he a ailable NMR da a en a i ely sugges ed he coo dina ion o bo h 1,2,3- iazole ings o he Ru–Cym uni as indica ed in Scheme 4. Al hough he coo dina ion p ope ies o he 1,2,3- iazole ni ogen a om N2 a e weak, some o us ha e p e iously shown ha such chela es can be g ea ly s abilized h ough an assis ance o auxilia y ligand [22]. Table 5. Selec ed 1H, 13C and 15N NMR chemical shi s in ppm o compounds 1and 7. 1a 1b 1c 1d 7a 7b 7c 7d Quinolone N1 – – – – – – 134.4 – C2 168.5 166.8 168.7 166.8 167.7 165.8 167.8 165.8 C3 72.2 80.0 71.9 79.7 72.6 79.6 72.8 80.0 C4 190.7 188.9 190.8 189.0 189.7 187.5 189.6 187.7 C4a 117.4 119.2 117.5 119.2 119.0 121.0 119.2 120.9 C5 127.7 127.6 127.6 127.5 128.2 129.2 128.0 127.8 C6 123.5 123.5 123.3 123.4 124.2 124.6 124.0 124.2 C7 137.3 137.0 137.1 136.9 137.3 136.9 137.1 136.7 C8 117.0 116.7 116.9 116.7 116.7 115.8 116.6 116.3 C8a 141.6 140.5 141.6 140.6 140.8 140.6 140.7 140.0 Ring A N1A– – – – – – 247.9 – N2A– – – – – – 363.4 – N3A– – – – – – 354.0 – C4A145.8 145.3 147.4 146.8 145.9 146.0 141.5 140.9 C5A122.4 123.4 123.7 124.8 122.5 122.3 126.0 127.1 H5A8.89 8.49 8.26 7.77 8.89 7.26 8.46 8.15 Molecules 2018,23, 2310 7 o 21 Table 6. Selec ed 1H, 13C and 15N NMR chemical shi s in ppm o compounds 2. 2a 2b 2c 2d 2e 2 2g 2h 2i 2j 2k 2l Quinolone N1 – 136.3 135.8 138.7 138.7 135.3 – – 137.5 140.4 140.4 138.9 C2 168.2 168.3 168.5 168.2 168.3 168.6 166.2 166.4 166.6 166.6 166.9 166.6 C3 72.8 73.0 73.0 71.6 71.5 73.3 80.1 80.3 80.4 79.6 79.6 79.7 C4 190.0 190.0 189.9 189.4 189.4 189.9 188.2 188.2 188.1 187.9 187.9 187.9 C4a 119.1 119.2 119.3 119.2 119.2 119.4 120.9 120.9 120.9 120.9 120.9 121.0 C5 128.1 128.1 128.1 129.3 129.4 127.9 127.9 127.9 127.9 129.0 129.1 129.1 C6 123.9 124.0 123.9 124.6 124.7 123.8 124.0 124.1 124.0 124.6 124.7 124.6 C7 137.2 137.3 137.2 137.8 137.8 137.0 136.8 136.8 136.8 137.2 137.4 137.2 C8 116.7 116.8 116.6 116.9 116.8 116.5 116.7 116.7 116.5 116.8 116.7 116.6 C8a 141.5 141.6 141.4 141.7 141.7 141.3 140.8 140.7 140.5 141.1 140.9 141.2 Ring A N1A– 248.9 248.9 248.4 248.8 247.6 – – 248.7 249.8 249.9 249.7 N2A– 363.2 363.4 361.6 – 363.7 – – 367.4 365.1 – – N3A– 347.1 347.1 355.2 355.5 353.4 – – 347.2 356.9 357.2 357.1 C4A145.9 146.0 146.0 142.3 142.3 141.6 145.4 145.4 145.4 140.9 140.9 140.9 C5A122.5 122.5 122.5 124.2 124.1 126.1 123.4 123.5 123.4 126.4 126.4 126.4 H5A8.87 8.87 8.87 7.78 7.86 8.47 8.51 8.54 8.58 7.08 7.14 7.13 Ring D N1D– 255.7 260.5 250.4 256.3 260.0 – – 260.4 250.4 256.3 261.2 N2D– 358.1 358.6 362.6 – 361.9 – – – 362.9 – – N3D– 353.4 356.9 350.0 351.9 356.5 – – 357.7 350.5 352.9 355.8 C4D142.2 143.3 143.2 142.9 143.2 143.2 141.9 142.9 143.0 142.9 143.2 143.0 C5D123.8 121.8 120.6 123.5 121.7 120.6 124.2 122.3 120.8 123.5 121.8 121.0 H5D8.16 8.75 8.82 7.55 8.10 8.82 8.24 8.83 8.81 7.58 8.05 8.63 Molecules 2018, 23, x FOR PEER REVIEW 8 o 21 A emp s o unambiguously de e mine he s uc u e o [Ru–Cym]-2b by a iable empe a u e NMR echniques, as well as o g ow c ys als sui able o X- ay, ailed. All o he abo e also applies o compounds 2g and 2h ha we e also p elimina ily es ed in [Ru–Cym] coo dina ion. 2b N O O N CH 3 N N NN N N O ON CH 3 NN N NN Ru Cl Ru Cl Ru Cl Cl Cl CDCl 3 NMR expe imen [Ru−Cym]- 2b 1/2 Scheme 4. Reac ion o 2b wi h [RuCl(μ-Cl)(η 6 -p-cymene)] 2 wi h en a i ely p oposed s uc u e o he [Ru–Cym]-2b complex. Figu e 3. A oma ic egion o 1 H NMR spec a o : (a) 2b in CDCl 3 , and (b) a mix u e o 2b (42 mM) and [RuCl(μ-Cl)(η 6 -p-cymene)] 2 (21 mM) in CDCl 3 immedia ely a e dissolu ion. Figu e 4. A oma ic egion o 13 C NMR spec a o : (a) 2b in CDCl 3 , and (b) a mix u e o 2b (42 mM) and [RuCl(μ-Cl)(η 6 -p-cymene)] 2 (21 mM) in CDCl 3 . 3. Ma e ials and Me hods 3.1. Gene al Expe imen al Me hods The eagen s and sol en s we e used as ob ained om he comme cial sou ces. Compounds 3a [14], 3b [14], and 5b [15], as well as benzyl azide (8a) [23], azidobenzene (8b) [11], and e azolo[1,5-a]py idine (8c) [24] we e p epa ed as desc ibed in he li e a u e. Column ch oma og aphy was ca ied ou on Fluka Silica gel 60 (pa icle size 0.063–0.2 mm, ac i i y acc. B ockmann and Schodde 2–3). Mel ing poin s we e de e mined on he mic oscope ho s age, Ko le , PolyThe m, manu ac u e Helmu Hund GmbH, We zla and a e unco ec ed. TLC was ca ied ou on p e-coa ed TLC shee s ALUGRAM ® SIL G/UV 254 o TLC, MACHEREY-NAGEL. NMR spec a Scheme 4. Reac ion o 2b wi h [RuCl( µ -Cl)( η6 -p-cymene)] 2 wi h en a i ely p oposed s uc u e o he [Ru–Cym]-2b complex. Molecules 2018, 23, x FOR PEER REVIEW 8 o 21 A emp s o unambiguously de e mine he s uc u e o [Ru–Cym]-2b by a iable empe a u e NMR echniques, as well as o g ow c ys als sui able o X- ay, ailed. All o he abo e also applies o compounds 2g and 2h ha we e also p elimina ily es ed in [Ru–Cym] coo dina ion. 2b N O O N CH 3 N N NN N N O ON CH 3 NN N NN Ru Cl Ru Cl Ru Cl Cl Cl CDCl 3 NMR expe imen [Ru−Cym]- 2b 1/2 Scheme 4. Reac ion o 2b wi h [RuCl(μ-Cl)(η 6 -p-cymene)] 2 wi h en a i ely p oposed s uc u e o he [Ru–Cym]-2b complex. Figu e 3. A oma ic egion o 1 H NMR spec a o : (a) 2b in CDCl 3 , and (b) a mix u e o 2b (42 mM) and [RuCl(μ-Cl)(η 6 -p-cymene)] 2 (21 mM) in CDCl 3 immedia ely a e dissolu ion. Figu e 4. A oma ic egion o 13 C NMR spec a o : (a) 2b in CDCl 3 , and (b) a mix u e o 2b (42 mM) and [RuCl(μ-Cl)(η 6 -p-cymene)] 2 (21 mM) in CDCl 3 . 3. Ma e ials and Me hods 3.1. Gene al Expe imen al Me hods The eagen s and sol en s we e used as ob ained om he comme cial sou ces. Compounds 3a [14], 3b [14], and 5b [15], as well as benzyl azide (8a) [23], azidobenzene (8b) [11], and e azolo[1,5-a]py idine (8c) [24] we e p epa ed as desc ibed in he li e a u e. Column ch oma og aphy was ca ied ou on Fluka Silica gel 60 (pa icle size 0.063–0.2 mm, ac i i y acc. B ockmann and Schodde 2–3). Mel ing poin s we e de e mined on he mic oscope ho s age, Ko le , PolyThe m, manu ac u e Helmu Hund GmbH, We zla and a e unco ec ed. TLC was ca ied ou on p e-coa ed TLC shee s ALUGRAM ® SIL G/UV 254 o TLC, MACHEREY-NAGEL. NMR spec a Figu e 3. A oma ic egion o 1 H NMR spec a o : ( a ) 2b in CDCl 3 , and ( b ) a mix u e o 2b (42 mM) and [RuCl(µ-Cl)(η6-p-cymene)]2(21 mM) in CDCl3immedia ely a e dissolu ion. Molecules 2018,23, 2310 8 o 21 Molecules 2018, 23, x FOR PEER REVIEW 8 o 21 A emp s o unambiguously de e mine he s uc u e o [Ru–Cym]-2b by a iable empe a u e NMR echniques, as well as o g ow c ys als sui able o X- ay, ailed. All o he abo e also applies o compounds 2g and 2h ha we e also p elimina ily es ed in [Ru–Cym] coo dina ion. 2b N O O N CH 3 N N NN N N O ON CH 3 NN N NN Ru Cl Ru Cl Ru Cl Cl Cl CDCl 3 NMR expe imen [Ru−Cym]- 2b 1/2 Scheme 4. Reac ion o 2b wi h [RuCl(μ-Cl)(η 6 -p-cymene)] 2 wi h en a i ely p oposed s uc u e o he [Ru–Cym]-2b complex. Figu e 3. A oma ic egion o 1 H NMR spec a o : (a) 2b in CDCl 3 , and (b) a mix u e o 2b (42 mM) and [RuCl(μ-Cl)(η 6 -p-cymene)] 2 (21 mM) in CDCl 3 immedia ely a e dissolu ion. Figu e 4. A oma ic egion o 13 C NMR spec a o : (a) 2b in CDCl 3 , and (b) a mix u e o 2b (42 mM) and [RuCl(μ-Cl)(η 6 -p-cymene)] 2 (21 mM) in CDCl 3 . 3. Ma e ials and Me hods 3.1. Gene al Expe imen al Me hods The eagen s and sol en s we e used as ob ained om he comme cial sou ces. Compounds 3a [14], 3b [14], and 5b [15], as well as benzyl azide (8a) [23], azidobenzene (8b) [11], and e azolo[1,5-a]py idine (8c) [24] we e p epa ed as desc ibed in he li e a u e. Column ch oma og aphy was ca ied ou on Fluka Silica gel 60 (pa icle size 0.063–0.2 mm, ac i i y acc. B ockmann and Schodde 2–3). Mel ing poin s we e de e mined on he mic oscope ho s age, Ko le , PolyThe m, manu ac u e Helmu Hund GmbH, We zla and a e unco ec ed. TLC was ca ied ou on p e-coa ed TLC shee s ALUGRAM ® SIL G/UV 254 o TLC, MACHEREY-NAGEL. NMR spec a Figu e 4. A oma ic egion o 13 C NMR spec a o : ( a ) 2b in CDCl 3 , and ( b ) a mix u e o 2b (42 mM) and [RuCl(µ-Cl)(η6-p-cymene)]2(21 mM) in CDCl3. A emp s o unambiguously de e mine he s uc u e o [Ru–Cym]- 2b by a iable empe a u e NMR echniques, as well as o g ow c ys als sui able o X- ay, ailed. All o he abo e also applies o compounds 2g and 2h ha we e also p elimina ily es ed in [Ru–Cym] coo dina ion. 3. Ma e ials and Me hods 3.1. Gene al Expe imen al Me hods The eagen s and sol en s we e used as ob ained om he comme cial sou ces. Compounds 3a [ 14 ], 3b [ 14 ], and 5b [ 15 ], as well as benzyl azide ( 8a ) [ 23 ], azidobenzene ( 8b ) [ 11 ], and e azolo[1,5-a]py idine ( 8c ) [ 24 ] we e p epa ed as desc ibed in he li e a u e. Column ch oma og aphy was ca ied ou on Fluka Silica gel 60 (pa icle size 0.063–0.2 mm, ac i i y acc. B ockmann and Schodde 2–3). Mel ing poin s we e de e mined on he mic oscope ho s age, Ko le , PolyThe m, manu ac u e Helmu Hund GmbH, We zla and a e unco ec ed. TLC was ca ied ou on p e-coa ed TLC shee s ALUGRAM ® SIL G/UV 254 o TLC, MACHEREY-NAGEL. NMR spec a we e eco ded wi h a B uke A ance III 500 MHz NMR ins umen ope a ing a 500 MHz ( 1 H), 126 MHz ( 13 C) and 51 MHz ( 15 N) a 300 K. P o on spec a we e e e enced o TMS as in e nal s anda d, in some cases o he esidual signal o DMSO-d 5 (a δ 2.50 ppm) o CHCl 3 (a δ 7.26 ppm). Ca bon chemical shi s we e de e mined ela i e o he 13 C signal o DMSO-d 6 (39.52 ppm) o CDCl 3 (77.16 ppm). 15 N chemical shi s we e ex ac ed om 1 H– 15 Ngs-HMBC spec a (wi h 20 Hz digi al esolu ion in he indi ec dimension and he pa ame e s adjus ed o a long- ange 1 H– 15 N coupling cons an o 5 Hz) de e mined wi h espec o ex e nal ni ome hane and a e co ec ed o ex e nal ammonia by addi ion o 380.5 ppm. Ni ogen chemical shi s a e epo ed o one decimal place as measu ed o he spec um, howe e , he da a should no be conside ed o be mo e accu a e han ± 0.5 ppm because o he digi al esolu ion limi s o he expe imen . Chemical shi s a e gi en on he δ scale (ppm). Coupling cons an s (J) a e gi en in Hz. Mul iplici ies a e indica ed as ollows: s (single ), d (double ), ( iple ), q (qua e ), m (mul iple ) o b (b oadened). In a ed spec a we e eco ded on FT-IR spec ome e Alpha (B uke Op ik GmbH E lingen, E lingen, Ge many) using samples in po assium b omide disks and only he s onges /s uc u ally mos impo an peaks a e lis ed. Elec on impac mass spec a (EI) we e eco ded on a Shimadzu QP–2010 ins umen a 70 eV. HRMS spec a we e eco ded wi h Agilen 6224 Accu a e Mass TOF LC/MS sys em wi h elec osp ay ioniza ion (ESI). Elemen al analyses (C, H, N) we e pe o med wi h FlashEA1112 Au oma ic Elemen al Analyse (The mo Fishe Scien i ic Inc., Wal ham, MA, USA). Molecules 2018,23, 2310 9 o 21 3.2. Gene al P ocedu e o he Syn hesis o 3-Chlo oquinoline-2,4(1H,3H)-Diones 4 (Scheme 1) The 3-Chlo oquinoline-2,4(1H,3H)-diones 4a [ 15 ] and 4b [ 16 ], we e p epa ed om 4-hyd oxyquinolin-2(1H)-ones 3a [ 14 ] and 3b [ 14 ], espec i ely, acco ding o he p ocedu es desc ibed in he li e a u e. 3-Chlo o-3-me hylquinoline-2,4(1H,3H)-dione (4a). Compound 4a (19.71 g, 94.0 mmol, 94%) was p epa ed om 3a (17.52 g, 100 mmol). Yellow c ys als, m.p. 178–181 ◦ C (benzene), m.p. [ 15 ] 172 ◦ C (ace ic acid—wa e ); R = 0.52 (30% e hyl ace a e in chlo o o m); 1 H NMR (500 MHz, CDCl 3 ) δ 1.99 (s, 3H), 7.06 (d, 1H, J= 8.0 Hz), 7.22 (dd, 1H, J= 7.6, 7.6 Hz), 7.59–7.66 (m, 1H), 8.02 (d, 1H, J= 7.7 Hz), 9.41 (s, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 21.2, 62.8, 116.7, 118.1, 124.5, 129.1, 136.8, 139.6, 169.2, 188.4; IR (cm −1 ): ν 3203, 3072, 3004, 2940, 1709, 1674, 1614, 1600, 1486, 1439, 1379, 1239, 770, 440; MS (EI) m/z (%): 212 (4, [M + 3] + ), 211 (33, [M ( 37 Cl)] + ), 210 (17, [M + 1] + ), 209 (100, [M ( 35 Cl)] + ), 208 (18), 175 (15), 174 (36), 146 (68), 128 (17), 120 (18), 119 (59), 92 (32), 91 (15); HRMS (ESI+): m/zcalcd o C 10 H 9 ClNO 2+ [M + H] + 210.0316, ound 210.0313. Anal. Calcd o C 10 H 8 ClNO 2 (209.63): C, 57.30; H, 3.85; N, 6.68%. Found: C, 57.18; H, 3.83; N, 6.61%. 3-Chlo o-3-phenylquinoline-2,4(1H,3H)-dione (4b). Compound 4b (26.08 g, 96.0 mmol, 96%) was p epa ed om 3b (23.73 g, 100 mmol). Pale yellow needles, m.p. 182–185 ◦ C (benzene), m.p. [ 16 ] 178–180 ◦ C (e hanol); R = 0.57 (30% e hyl ace a e in chlo o o m). 1 H NMR (500 MHz, CDCl 3 ) δ 7.04 (d, 1H, J= 8.0 Hz, H-8), 7.18 (ddd, 1H, J= 7.8, 7.4, 0.7 Hz, H-6), 7.33–7.39 (m, 3H, H-3 C , H-4 C , H-5 C ), 7.51–7.54 (m, 2H, H-2 C , H-6 C ), 7.55 (ddd, 1H, J= 7.3, 6.5, 1.5 Hz, H-7), 7.97 (dd, 1H, J= 7.8, 1.2 Hz, H-5), 9.82 (s, 1H, H-1); 13 C NMR (126 MHz, CDCl 3 ) δ 74.9 (C-3), 116.9 (C-8), 118.7 (C-4a), 124.7 (C-6), 127.4 (C-2 C , C-6 C ), 129.1 (C-5), 129.2 (C-3 C , C-5 C ), 129.8 (C-4 C ), 134.6 (C-1 C ), 137.0 (C-7), 139.4 (C-8a), 168.8 (C-2), 187.9 (C-4); IR (cm −1 ): ν 3201, 3138, 3082, 2992, 2926, 1716, 1680, 1613, 1595, 1485, 1365, 755, 743, 690; MS (EI) m/z(%): 273 (7, [M ( 37 Cl)] + ), 271 (21, [M ( 35 Cl)] + ), 238 (12), 237 (80), 236 (100), 218 (10), 120 (63), 119 (19), 92 (34), 89 (10), 77 (12), 76 (10), 65 (14), 63 (10); HRMS (ESI+): m/zcalcd o C 15 H 11 ClNO 2+ [M + H] + 272.0473, ound 272.0480. Anal. Calcd o C 15 H 10 ClNO 2 (271.70): C, 66.31; H, 3.71; N, 5.16%. Found: C, 66.07; H, 3.62; N, 5.29%. 3.3. Gene al P ocedu e o he Syn hesis o 3-Azidoquinoline-2,4(1H,3H)-Diones 5 (Scheme 1) To a s i ed solu ion o he 3-chlo oquinoline-2,4(1H,3H)-dione 4 (40 mmol) in DMF (200 mL), sodium azide (3.90 g, 60 mmol) was added in small po ions du ing 10 min. The eac ion mix u e was s i ed in da kness o addi ional 2 h and hen pou ed in o ice-wa e (1.5 L). The p ecipi a ed solid was il e ed, washed wi h wa e and d ied a 50 ◦ C in da kness, which a o ded p oduc 5 , pu e acco ding o TLC and 1H NMR spec um, which was c ys allized om benzene. 3-Azido-3-me hylquinoline-2,4(1H,3H)-dione (5a). Compound 5a (8.47 g, 39.2 mmol, 98%) was p epa ed om 4a (8.39 g, 40.0 mmol). Colo less needles, m.p. 158–161 ◦ C (benzene, 87% yield o ec ys alliza ion); R = 0.30 (30% e hyl ace a e in chlo o o m). 1 H NMR (500 MHz, CDCl 3 ) δ 1.86 (s, 3H, CH 3 ), 7.11 (d, 1H, J= 8.0 Hz, H-8), 7.22 (dd, 1H, J= 7.4, 7.4 Hz, H-6), 7.60–7.67 (m, 1H, H-7), 7.98 (d, 1H, J= 7.3 Hz, H-5), 9.86 (s, 1H, H-1); 13 C NMR (126 MHz, CDCl 3 ) δ 23.6 (CH 3 ), 70.0 (C-3), 116.9 (C-8), 118.0 (C-4a), 124.6 (C-6), 128.6 (C-5), 137.2 (C-7), 140.0 (C-8a), 171.6 (C-2), 191.7 (C-4); IR (cm −1 ): ν 3202, 3078, 3005, 2936, 2108, 1708, 1682, 1614, 1598, 1485, 1392, 1284, 1156, 755, 612; MS (EI) m/z(%): 217 (0.24, [M + 1] + ), 216 (2, [M] + ), 147 (15), 120 (11), 119 (100), 92 (35), 91 (11), 64 (12); HRMS (ESI+): m/zcalcd o C 10 H 9 N 4 O 2+ [M + H] + 217.0720, ound 217.0724. Anal. Calcd o C 10 H 8 N 4 O 2 (216.20): C, 55.55; H, 3.73; N, 25.91%. Found: C, 55.44; H, 3.72; N, 25.98%. 3-Azido-3-phenylquinoline-2,4(1H,3H)-dione (5b). Compound 5b (10.90 g, 39.2 mmol, 98%) was p epa ed om 4b (10.87 g, 40.0 mmol). Colo less needles, m.p. 186–189 ◦ C (benzene, 96% yield o ec ys alliza ion); m.p. [ 9 ] 173–181 ◦ C (benzene); R = 0.33 (38% e hyl ace a e in pe oleum e he ); 1 H NMR (500 MHz, CDCl 3 ) δ 6.98 (d, 1H, J= 8.1 Hz, H-8), 7.16 (dd, 1H, J= 7.6, 7.6 Hz, H-6), 7.38–7.43 (m, 3H, H-3 C , H-4 C , H-5 C ), 7.48–7.53 (m, 2H, H-2 C , H-6 C ), 7.54 (ddd, 1H, J= 7.7, 7.7, 1.6 Hz, H-7), Molecules 2018,23, 2310 16 o 21 129.7 (C-1 C ), 130.0 (C-3 C , C-5 C ), 131.3 (C-4 C ), 134.5 (C-1 E ), 137.2 (C-7), 140.9 (C-4 A ), 141.1 (C-8a), 142.9 (C-4 D ), 166.6 (C-2), 171.0 (COCH 3 ), 187.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 140.4 (N-1), 249.8 (N-1 A ), 250.4 (N-1 D ), 350.5 (N-3 D ), 356.9 (N-3 A ), 362.9 (N-2 D ), 365.1 (N-2 A ); IR (cm −1 ): ν 3142, 2927, 1740, 1717, 1679, 1602, 1469, 1377, 1244, 768, 749, 714, 697; MS (EI) m/z(%): 548 (0.1, [M + 1] + ), 547 (0.3, [M] + ), 347 (13), 289 (13), 144 (14), 105 (10), 104 (13), 91 (100), 43 (29); HRMS (ESI+): m/zcalcd o C 30 H 26 N 7 O 4+ [M + H]+548.2041, ound 548.2032. (1-(2,4-Dioxo-3-phenyl-1-((1-phenyl-1H-1,2,3- iazol-4-yl)me hyl)-1,2,3,4- e ahyd oquinolin-3-yl)- 1H-1,2,3- iazol-4-yl)me hyl ace a e (2k). Colo less powde , m.p. 93–105 ◦ C; R = 0.42 (30% e hyl ace a e in chlo o o m); 1 H NMR (500 MHz, CDCl 3 ) δ 2.05 (s, 3H, CH 3 ), 5.19 (s, 2H, OCH 2 ), 5.42 (d, 1H, J= 15.7 Hz, N-1–CH α ), 5.55 (d, 1H, J= 15.7 Hz, N-1–CH β ), 7.14 (s, 1H, H-5 A ), 7.20 (ddd, 1H, J= 7.6, 7.6, 0.8 Hz, H-6), 7.38–7.49 (m, 6H, H-2 C , H-3 C , H-4 C , H-5 C , H-6 C , H-4 E ), 7.49–7.55 (m, 2H, H-3 E , H-5 E ), 7.66 (ddd, 1H, J= 8.5, 7.3, 1.7 Hz, H-7), 7.68–7.72 (m, 2H, H-2 E , H-6 E ), 7.76 (d, 1H, J= 8.4 Hz, H-8), 8.03 (dd, 1H, J= 7.8, 1.5 Hz, H-5), 8.05 (s, 1H, H-5 D ); 13 C NMR (126 MHz, CDCl 3 ) δ 21.0 (CH 3 ), 39.8 (N-1-CH 2) , 57.6 (OCH 2 ), 79.6 (C-3), 116.7 (C-8), 120.7 (C-2 E , C-6 E ), 120.9 (C-4a), 121.8 (C-5 D ), 124.7 (C-6), 126.4 (C-5 A ), 128.9 (C-2 C , C-6 C ), 129.1 (C-5), 129.2 (C-4 E ), 129.9 (C-1 C ), 130.0 (C-3 E , C-5 E ), 130.2 (C-3 C , C-5 C ), 131.4 (C-4 C ), 136.9 (C-1 E ), 137.4 (C-7), 140.9 (C-4 A ), 140.9 (C-8a), 143.2 (C-4 D ), 166.9 (C-2), 171.0 (COCH 3 ), 187.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 140.4 (N-1), 249.9 (N-1 A ), 256.3 (N-1 D ), 352.9 (N-3 D ), 357.2 (N-3 A ); IR (cm −1 ): ν 3146, 2962, 1741, 1718, 1681, 1600, 1468, 1376, 1243, 1043, 762, 693, 665, 608; MS (EI) m/z(%): 534 (0.2, [M + 1] + ), 533 (0.6, [M] + ), 366 (12), 365 (11), 262 (12), 131 (11), 130 (100), 129 (19), 128 (12), 104 (14), 103 (16), 99 (18), 77 (62), 44 (17), 43 (52); HRMS (ESI+): m/zcalcd o C29H24N7O4+[M + H]+534.1884, ound 534.1882. 3.9. Gene al P ocedu e o he Syn hesis o Bis-T iazoles 2c, ,i,l by Employing CuSO4/Cu0/DMF Condi ions (Table 4, En ies 3, 9, 12 and 15) A mix u e o he app op ia e N-p opa gylquinoline-2,4(1H,3H)-dione 7 (1.5 mmol), e azolo[1,5-a]py idine (189 mg, 1.58 mmol), CuSO 4· 5H 2 O (38 mg, 0.15 mmol), g anula coppe (191 mg, 3.05 mmol) and DMF (9 mL) was hea ed in da kness o 95–105 ◦ C (oil ba h) o he ime gi en in Table 4, whe eas he colo o he mix u e changed om b own-black o da k g een. The mix u e was hen allowed o cool o oom empe a u e. Subsequen ly, (NH 4 ) 2 CO 3 (432 mg, 4.5 mmol) and wa e (2 mL) we e added and a e s i ing o 15 min, he mix u e was pou ed in o a na ow (1 cm diame e ) column o silica gel (15 g). The o ganic po ion was elu ed om he column wi h 10% e hanol in chlo o o m. The yellow elua e was washed wi h sa u a ed aqueous NH 4 Cl (50 mL), d ied o e anhyd ous sodium sul a e, il e ed, and he sol en was emo ed by o a y e apo a ion in acuo. In he cases o 2c , i , he esidue, which was TLC pu e compound, was c ys allized om sui able sol en . In he cases o 2 , l , he esidue was pu i ied by ch oma og aphy on silica gel column using chlo o o m as eluen . The yields o p epa ed compounds 2a e gi en in Table 4. 3-Me hyl-3-(4-phenyl-1H-1,2,3- iazol-1-yl)-1-((1-(py idin-2-yl)-1H-1,2,3- iazol-4-yl)me hyl)quinoline- 2,4(1H,3H)-dione (2c). Colo less c ys als, m.p. 188–191 ◦ C (benzene); R = 0.29 (30% e hyl ace a e in chlo o o m); 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.23 (s, 3H, CH 3 ), 5.42 (d, 1H, J= 16.5 Hz, N-1–CH α ), 5.58 (d, 1H, J= 16.5 Hz, N-1–CH β ), 7.28–7.40 (m, 2H, H-6, H-4 B ), 7.43–7.51 (m, 2H, H-3 B , H-5 B ), 7.51–7.57 (m, 1H, H-5 E ), 7.64 (d, 1H, J= 8.4 Hz, H-8), 7.78–7.90 (m, 3H, H-7, H-2 B , H-6 B ), 7.99 (d, 1H, J= 7.5 Hz, H-5), 8.07–8.17 (m, 2H, H-3 E , H-4 E ), 8.54–8.61 (m, 1H, H-6 E ), 8.82 (s, 1H, H-5 D ), 8.87 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO-d 6 ) δ 23.4 (CH 3 ), 38.7 (N-1–CH 2 ), 73.0 (C-3), 113.7 (C-3 E ), 116.6 (C-8), 119.3 (C-4a), 120.6 (C-5 D ), 122.5 (C-5 A ), 123.9 (C-6), 124.5 (C-5 E ), 125.2 (C-2 B , C-6 B ), 128.1 (C-4 B ), 128.1 (C-5), 129.1 (C-3 B , C-5 B ), 130.5 (C-1 B ), 137.2 (C-7), 140.3 (C-4 E ), 141.4 (C-8a), 143.2 (C-4 D ), 146.0 (C-4 A ), 148.4 (C-2 E ), 149.0 (C-6 E ), 168.5 (C-2), 189.9 (C-4); 15 N NMR (51 MHz, DMSO-d 6 ) δ 135.8 (N-1), 248.9 (N-1 A ), 260.5 (N-1 D ), 284.9 (N-1 E ), 347.1 (N-3 A ), 356.9 (N-3 D ), 358.6 (N-2 D ), 363.4 (N-2 A ); IR (cm −1 ): ν 3426, 3126, 2972, 1706, 1674, 1601, 1471, 1378, 1310, 1232, 1041, 777, 764; MS (EI) m/z(%): 477 (2, [M + 1] + ), 476 (7, [M] + ), 289 (11), 145 (14), 132 (14), 131 (96), 116 (50), 102 (10), 90 (10), 89 (13), 79 (20), Molecules 2018,23, 2310 17 o 21 78 (100), 77 (10), 51 (10); HRMS (ESI+): m/zcalcd o C 26 H 21 N 8 O 2+ [M + H] + 477.1782, ound 477.1773. Anal. Calcd o C 26 H 20 N 8 O 2 (476.48) C, 65.54; H, 4.23; N, 23.52%. Found: C, 65.68; H, 4.21; N, 23.63%. (1-(3-Me hyl-2,4-dioxo-1-((1-(py idin-2-yl)-1H-1,2,3- iazol-4-yl)me hyl)-1,2,3,4- e ahyd oquinolin- 3-yl)-1H-1,2,3- iazol-4-yl)me hyl ace a e (2 ). Colo less powde , m.p. 69–82 ◦ C; R = 0.29 (30% e hyl ace a e in chlo o o m); 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.06 (s, 3H, COCH 3 ), 2.18 (s, 3H, C3–CH 3 ), 5.17 (d, 1H, J= 12.7 Hz, O–CH α ), 5.20 (d, 1H, J= 12.7 Hz, O–CH β ), 5.41 (d, 1H, J= 16.5 Hz, N-1–CH α ), 5.53 (d, 1H, J= 16.5 Hz, N-1–CH β ), 7.31 (dd, 1H, J= 7.4, 7.4 Hz, H-6), 7.54 (dd, 1H, J= 8.8, 4.5 Hz, H-5 E ), 7.59 (d, 1H, J= 8.5 Hz, H-8), 7.77–7.83 (m, 1H, H-7), 7.96 (dd, 1H, J= 7.7 Hz, J= 1.6 Hz, H-5), 8.08–8.14 (m, 2H, H-3 E , H-4 E ), 8.47 (s, 1H, H-5 A ), 8.55–8.59 (m, 1H, H-6 E ), 8.82 (s, 1H, H-5 D ); 13 C NMR (126 MHz, DMSO-d 6 ) δ 20.6 (COCH 3 ), 23.5 (C3–CH 3 ), 38.7 (N-1–CH 2 ), 57.2 (OCH 2 ), 73.3 (C-3), 113.7 (C-3 E ), 116.5 (C-8), 119.4 (C-4a), 120.6 (C-5 D ), 123.8 (C-6), 124.4 (C-5 E ), 126.1 (C-5 A ), 127.9 (C-5), 137.0 (C-7), 140.2 (C-4 E ), 141.3 (C-8a), 141.6 (C-4 A ), 143.2 (C-4 D ), 148.3 (C-2 E ), 148.9 (C-6 E ), 168.6 (C-2), 170.1 (COCH 3 ), 189.9 (C-4); 15 N NMR (51 MHz, DMSO-d 6 ) δ 135.3 (N1), 247.6 (N-1 A ), 260.0 (N-1 D ), 284.7 (N-1 E ), 353.4 (N-3 A ), 356.5 (N-3 D ), 361.9 (N-2 D ), 363.7 (N-2 A ); IR (cm −1 ): ν 3152, 1741, 1718 1681, 1600, 1471, 1384, 1314, 1242, 1183, 1038, 782, 756, 663; MS (EI) m/z(%): 473 (0.7, [M + 1] + ), 472 (2, [M] + ), 304 (27), 303 (26), 302 (17), 132 (13), 131 (100), 79 (22), 78 (100), 43 (21); HRMS (ESI+): m/zcalcd o C 23 H 21 N 8 O 4+ [M + H] + 473.1680, ound 473.1684. Anal. Calcd o C 23 H 20 N 8 O 4·1 2 H 2 O (472.46): C, 57.38; H, 4.40; N, 23.27%. Found: C, 57.39; H, 4.36; N, 23.47%. 3-Phenyl-3-(4-phenyl-1H-1,2,3- iazol-1-yl)-1-((1-(py idin-2-yl)-1H-1,2,3- iazol-4-yl)me hyl)quinoline- 2,4(1H,3H)-dione (2i). Colo less c ys als, m.p. 188–192 ◦ C (benzene); R = 0.50 (30% e hyl ace a e in chlo o o m); 1 H NMR (500 MHz, DMSO-d 6 ) δ 5.44 (d, 1H, J= 16.3 Hz, N-1–CH α ), 5.67 (d, 1H, J= 16.3 Hz, N-1–CH β ), 7.26 (dd, 1H, J= 7.5, 7.5 Hz, H-6), 7.32–7.40 (m, 3H, H-4 B , H-2 C , H-6 C ), 7.41–7.52 (m, 5H, H-3 B , H-5 B , H-3 C , H-4 C , H-5 C ), 7.52–7.61 (m, 2H, H-8, H-5 E ), 7.68–7.75 (m, 1H, H-7), 7.78–7.86 (m, 2H, H-2 B , H-6 B ), 7.96 (dd, 1H, J= 7.7, 1.5 Hz, H-5), 8.09–8.16 (m, 2H, H-3 E , H-4 E ), 8.58 (s, 1H, H-5 A ), 8.60 (ddd, 1H, J= 4.8, 1.3, 1.3 Hz, H-6 E ), 8.81 (s, 1H, H-5 D ); 13 C NMR (126 MHz, DMSO-d 6 ) δ 39.1 (N-1–CH 2 ), 80.4 (C-3), 113.7 (C-3 E ), 116.5 (C-8), 120.8 (C-5 D ), 120.9 (C-4a), 123.4 (C-5 A ), 124.0 (C-6), 124.5 (C-5 E ), 125.2 (C-2 B , C-6 B ), 127.9 (C-5), 128.0 (C-4 B ), 128.9 (C-2 C , C-6 C ), 129.0 (C-3 B , C-5 B ), 129.4 (C-3 C , C-5 C ), 130.0 (C-1 C ), 130.5 (C-4 C ), 130.6 (C-1 B ), 136.8 (C-7), 140.2 (C-4 E ), 140.5 (C-8a), 143.0 (C-4 D ), 145.4 (C-4 A ), 148.3 (C-2 E ), 149.0 (C-6 E ), 166.6 (C-2), 188.1 (C-4); 15 N NMR (51 MHz, DMSO-d 6 ) δ 137.5 (N1), 248.7 (N-1 A ), 260.4 (N-1 D ), 284.8 (N-1 E ), 347.2 (N-3 A ), 357.7 (N-3 D ), 367.4 (N-2 A ); IR (cm −1 ): ν 3418, 2973, 1718, 1679, 1596, 1477, 1467, 1450, 1049, 1031, 773, 766, 757, 701; MS (EI) m/z(%): 539 (1, [M + 1] + ), 538 (3, [M] + ), 236 (11), 145 (16), 132 (14), 131 (100), 116 (32), 91 (11), 89 (11), 79 (15), 78 (85), 77 (13); HRMS (ESI+): m/zcalcd o C 31 H 23 N 8 O 2+ [M + H] + 539.1938, ound 539.1932. Anal. calcd o C31H22N8O2(538.19): C, 69.13; H, 4.12; N, 20.81%. Found: C, 68.91; H, 4.17; N, 20.66%. (1-(2,4-Dioxo-3-phenyl-1-((1-(py idin-2-yl)-1H-1,2,3- iazol-4-yl)me hyl)-1,2,3,4- e ahyd oquinolin- 3-yl)-1H-1,2,3- iazol-4-yl)me hyl ace a e (2l). Colo less powde , m.p. 93–102 ◦ C; R = 0.18 (30% e hyl ace a e in chlo o o m); 1 H NMR (500 MHz, CDCl 3 ) δ 2.05 (s, 3H, COCH 3 ), 5.19 (s, 2H, OCH 2 ), 5.30 (d, 1H, J= 15.8 Hz, N-1–CH α ), 5.71 (d, 1H, J= 15.8 Hz, N-1–CH β ), 7.13 (s, 1H, H-5 A ), 7.19 (dd, 1H, J= 7.5, 7.5 Hz, H-6), 7.36 (dd, 1H, J= 7.3, 4.9 Hz, H-5 E ), 7.38–7.42 (m, 2H, H-3 C , H-5 C ), 7.42–7.48 (m, 3H, H-2 C , H-4 C , H-6 C ), 7.63 (ddd, 1H, J= 8.3, 7.4, 1.6 Hz, H-7), 7.70 (d, 1H, J= 8.4 Hz, H-8), 7.88–7.95 (m, 1H, H-4 E ), 8.02 (dd, 1H, J= 7.8, 1.5 Hz, H-5), 8.15 (d, 1H, J= 8.2 Hz, H-3 E ), 8.47–8.53 (m, 1H, H-6 E ), 8.63 (s, 1H, H-5 D ); 13 C NMR (126 MHz, CDCl 3 ) δ 21.0 (COCH 3 ), 39.9 (N-1–CH 2 ), 57.6 (OCH 2 ), 79.7 (C-3), 113.9 (C-3 E ), 116.6 (C-8), 121.0 (C-4a), 121.0 (C-5 D ), 124.0 (C-5 E ), 124.6 (C-6), 126.4 (C-5 A ), 128.9 (C-2 C , C-6 C ), 129.1 (C-5), 129.7 (C-1 C ), 130.2 (C-3 C , C-5 C ), 131.3 (C-4 C ), 137.2 (C-7), 139.3 (C-4 E ), 140.9 (C-4 A ), 141.2 (C-8a), 143.0 (C-4 D ), 148.9 (C-6 E ), 149.0 (C-2 E ), 166.6 (C-2), 171.0 (COCH 3 ), 187.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 138.9 (N-1), 249.7 (N-1 A ), 261.2 (N-1 D ), 285.1 (N-1 E ), 355.8 (N-3 D ), 357.1 (N-3 A ); IR (cm −1 ): ν 3155, 2926, 1741, 1718, 1682, 1599, 1470, 1375, 1313, 1243, 1034, 779, 697, 665; MS (EI) m/z(%): 535 (0.4, [M + 1] + ), 534 (0.7, [M] + ), 132 (14), 131 (100), 79 (19), 78 (93), 44 (11), 43 (31); HRMS (ESI+): m/zcalcd o C28H23N8O4+[M + H]+535.1837, ound 535.1846. Molecules 2018,23, 2310 18 o 21 3.10. Syn hesis o Bis-T iazole 2d by Employing CH2Cl2/Wa e /CuSO4·5H2O/Na-Asco ba e Condi ions (Table 4, En y 5) To a solu ion o ace ylene 7c (132 mg, 0.375 mmol) and azide 8a (52.4 mg, 0.394 mmol) in dichlo ome hane (6.5 mL) a solu ion o sodium asco ba e (59.5 mg, 0.3 mmol) in wa e (5.5 mL), and a solu ion o CuSO 4· 5H 2 O (7.5 mg, 0.03 mmol) in wa e (1 mL) we e added. The wo-phase liquid eac ion mix u e was s i ed in da kness a oom empe a u e un il he compound 7c eac ed comple ely acco ding o TLC analysis (4 h). The eac ion mix u e was dilu ed wi h wa e (50 mL) and ex ac ed wi h chlo o o m (4 × 30 mL). The combined o ganic laye s we e d ied (Na 2 SO 4 ), il e ed, and e apo a ed o d yness. The esidue was dissol ed in chlo o o m (5 mL) and subjec ed o silica gel (25 g) column ch oma og aphy using 67% e hyl ace a e in pe oleum e he as eluen , a o ding p oduc 2d (155 mg, 0.32 mmol, 85%). 3.11. Syn hesis o Bis-T iazole 2d by Employing -BuOH/Wa e /CH3CN/CuSO4·5H2O/Na-Asco ba e Condi ions (Table 4, En y 6) To a mix u e o ace ylene 7c (264 mg, 0.75 mmol), azide 8a (105 mg, 0.79 mmol) and -BuOH (3.5 mL) a solu ion o Na-asco ba e (30 mg, 0.15 mmol) in wa e (2.5 mL), and a solu ion o CuSO 4· 5H 2 O (4 mg, 0.02 mmol) in wa e (1 mL) we e added. The eac ion mix u e was s i ed in da kness a oom empe a u e o 9 h. Then a solu ion o Na-asco ba e (89 mg, 0.45 mmol) in wa e (1 mL), and a solu ion o CuSO 4· 5H 2 O (11 mg, 0.044 mmol) in wa e (1 mL) and -BuOH (2 mL) we e added. The eac ion mix u e was s i ed o addi ional 20 h. The esul ing s icky sedimen ha o med in he cou se o he eac ion was dissol ed by addi ion o ace oni ile (3 mL) o he eac ion mix u e. The eac ion mix u e was s i ed o addi ional 19 h. Al hough he azide and ace ylene coupling pa ne s we e s ill p esen in he eac ion mix u e, as judged by TLC analysis, he eac ion was s opped by he addi ion o wa e (50 mL) and ex ac ed wi h chlo o o m (4 × 30 mL). The combined o ganic laye s we e d ied (Na 2 SO 4 ), il e ed, and e apo a ed o d yness. The esidue was dissol ed in chlo o o m and subjec ed o silica gel (35 g) column ch oma og aphy using 67% e hyl ace a e in pe oleum e he as eluen , a o ding egene a ed s a ing ace ylene 7c (48 mg, 0.14 mmol, 18%) and p oduc 2d (295 mg, 0.61 mmol, 81%). 3.12. Syn hesis o Bis-T iazole 2d by Employing -BuOH/Wa e /CuSO4·5H2O/L-Asco bic Acid Condi ions (Table 4, En y 7) To a mix u e o ace ylene 7c (264 mg, 0.75 mmol) and azide 8a (105 mg, 0.79 mmol) a solu ion o L-asco bic acid (13 mg, 0.074 mmol) and CuSO 4· 5H 2 O (2 mg, 0.008 mmol) in wa e (3.5 mL), and -BuOH (3.5 mL) we e added. The eac ion mix u e was s i ed in da kness a oom empe a u e. A e 8.5 h and 22 h o s i ing addi ional po ions o L-asco bic acid/CuSO 4· 5H 2 O/wa e / -BuOH (40 mg, 0.23 mmol/6 mg, 0.02 mmol/1 mL/1 mL and 53 mg, 0.3 mmol/7.5 mg, 0.03 mmol/1 mL/1 mL, espec i ely) we e added. Al hough a e s i ing o addi ional 23 h ( o al eac ion ime 45 h), TLC analysis indica ed he p esence o azide and ace ylene s a ing compounds, he he e ogeneous eac ion mix u e (a s icky sedimen was o med) was dilu ed wi h wa e and ex ac ed wi h chlo o o m (5 × 50 mL). The combined o ganic laye s we e d ied (Na 2 SO 4 ), il e ed, and e apo a ed o d yness. The esidue was dissol ed in chlo o o m (5 mL) and subjec ed o silica gel (35 g) column ch oma og aphy using 33% e hyl ace a e in pe oleum e he as eluen , a o ding egene a ed s a ing ace ylene 7c (114 mg, 0.32 mmol, 43%) and p oduc 2d (165 mg, 0.34 mmol 45%). 3.13. 3-Azido-3-me hyl-1-(p op-2-yn-1-yl)Quinoline-2,4(1H,3H)-Dione (9a) (Scheme 3) A mix u e o he azide 5a (649 mg, 3.0 mmol) and po assium ca bona e (1.24 g, 9 mmol) in DMF (15 mL) was s i ed a oom empe a u e in da kness o 40 min. P opa gyl b omide ( 6c , 80% solu ion in oluene, 669 mg, 4.5 mmol) dilu ed wi h DMF (7 mL) was added d opwise unde s i ing du ing 1 min. The eac ion mix u e was s i ed o 6 h, du ing which ime i u ned yellow, dilu ed wi h cold wa e (200 mL) and ex ac ed wi h chlo o o m (5 × 50 mL). The combined o ganic laye s we e d ied (Na 2 SO 4 ), il e ed, and e apo a ed o d yness. T ace amoun s o DMF we e emo ed by i e Molecules 2018,23, 2310 19 o 21 subsequen co-des ila ions in acuo a 50 ◦ C wi h oluene (30 mL). The esidual yellow oil was dissol ed in chlo o o m (5 mL) and ch oma og aphed on column silica gel (35 g) using chlo o o m as eluen , a o ding p oduc 9a (717 mg, 2.82 mmol, 94%, d ied in acuo o cons an weigh ) as o -whi e oily ma e ial, ha was pu e by TLC (R = 0.57; chlo o o m); 1 H NMR (500 MHz, CDCl 3 ) δ 1.79 (s, 3H), 2.29 (dd, 1H, J= 2.5, 2.5 Hz), 4.67 (dd, 1H, J= 17.8, 2.5 Hz), 4.98 (dd, 1H, J= 17.8, 2.5 Hz), 7.26 (ddd, 1H, J= 7.7, 7.4, 0.8 Hz), 7.35 (d, 1H, J= 8.3 Hz), 7.71 (ddd, 1H, J= 8.3, 7.4, 1.7 Hz), 8.02 (dd, 1H, J= 7.7, 1.7 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 23.6, 32.7, 70.7, 73.4, 77.1, 115.8, 119.6, 124.4, 129.0, 136.9, 140.8, 169.1, 191.1; IR (cm −1 ): ν 3241, 2980, 2138, 2107, 1711, 1678, 1603, 1471, 1383, 1366, 1305, 1285, 1260, 1218, 762; HRMS (ESI+): m/zcalcd o C 13 H 11 N 4 O 2+ [M + H] + 255.0877, ound 255.0877; calcd o C13H11N2O2+[M −N2+ H]+227.0815, ound 227.0814. 3.14. Syn hesis o T iazole 7a om Phenylace ylene (6a) and Compound 9a (Scheme 3) A mix u e o compound 9a (286 mg, 1.13 mmol), phenylace ylene ( 6a ) (230 mg, 2.25 mmol), CuSO 4 5H 2 O (28 mg, 0.11 mmol) and g anula coppe (143 mg, 2.25 mmol) in DMF (5 mL) was s i ed in da kness a oom empe a u e o 60 min. To he esul ing b own-g een suspension (NH 4 ) 2 CO 3 (324 mg, 3.38 mmol) and wa e (3 mL) we e added and s i ing was con inued o 10 min. The esul ing mix u e was dilu ed wi h 10% e hanol in chlo o o m (10 mL). The o ganic laye was sepa a ed and he aqueous laye was ex ac ed wi h chlo o o m (3 × 10 mL). The combined o ganic laye s we e passed h ough a na ow (1 cm in diame e ) column o silica gel (13 g) and he column was subsequen ly washed wi h 10% e hanol in chlo o o m (210 mL) using o e p essu e o he op o he column. The yellow elua e was washed wi h sa u a ed aqueous NH 4 Cl (1 × 50 mL) and dis illed wa e (1 × 50 mL), d ied (Na 2 SO 4 ), il e ed, and e apo a ed o d yness. T ace amoun s o DMF we e emo ed by i e subsequen co-des ila ions in acuo a 50 ◦ C wi h oluene (40 mL). The esidue was ch oma og aphed on a column o silica gel (30 g) using 38% e hyl ace a e in hexane. The esul ing whi e solid (88 mg) was c ys allized om benzene a o ding iazole 7a (66 mg, 0.19 mmol, 16%), which was iden i ied wi h he compound 7a desc ibed abo e. 3.15. 3-Azido-1-((1-Benzyl-1H-1,2,3-T iazol-4-yl)Me hyl)-3-Me hylquinoline-2,4(1H,3H)-Dione (10a) (Scheme 3) A mix u e o ace ylene 9a (254 mg, 1.0 mmol), (azidome hyl)benzene ( 8a ) (266 mg, 2.0 mmol), CuSO 4· 5H 2 O (25 mg, 0.1 mmol) and g anula coppe (127 mg, 2.0 mmol) in DMF (10 mL) was s i ed a oom empe a u e o 21 h. Then (NH 4 ) 2 CO 3 (288 mg, 3.0 mmol) and wa e (3 mL) we e added and he s i ing was con inued o 10 min. The esul ing mix u e was pou ed in o a na ow (1 cm in diame e ) column o silica gel (13 g). The o ganic po ion was elu ed wi h 10% e hanol in chlo o o m (190 mL). The yellow elua e was washed wi h sa u a ed aqueous NH 4 Cl (50 mL) and wa e (50 mL), d ied (Na 2 SO 4 ), il e ed, and e apo a ed o d yness. T ace amoun s o DMF we e emo ed by six subsequen co-des ila ions in acuo a 50 ◦ C wi h oluene (30 mL). The esidue was dissol ed in chlo o o m (5 mL) and ch oma og aphed on silica gel (35 g) column using g adually 38% and 50% e hyl ace a e in pe oleum e he as mobile phase, a o ding p oduc 10a (164 mg, 0.42 mmol, 42%) as a whi e solid, m.p. 42–47 ◦ C; R = 0.21 (38% e hyl ace a e in pe oleum e he ); 1 H NMR (500 MHz, CDCl 3 ) δ 1.73 (s, 3H), 5.20 (d, 1H, J= 15.6 Hz), 5.31 (d, 1H, J= 15.6 Hz), 5.45 (d, 1H, J= 14.8 Hz), 5.49 (d, 1H, J= 14.8 Hz), 7.16–7.28 (m, 3H), 7.32–7.39 (m, 3H), 7.54 (s, 1H), 7.67 (ddd, 1H, J= 8.3, 7.4, 1.6 Hz), 7.77 (d, 1H, J= 8.4 Hz), 7.96 (dd, 1H, J= 7.7, 1.5 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 23.6, 39.1, 54.5, 70.6, 116.6, 119.5, 123.5, 124.3, 128.3, 128.8, 129.0, 129.3, 134.3, 137.1, 141.4, 143.0, 169.8, 191.3; IR (cm −1 ): ν 3137, 3033, 2980, 2106, 1713, 1676, 1602, 1489, 1469, 1379, 1336, 1279, 1223, 765, 724; HRMS (ESI+): m/zcalcd o C 20 H 18 N 7 O 2+ [M + H] + 388,1516, ound 388.1514. Anal. Calcd o C 20 H 17 N 7 O 2 (387.39): C, 62.01; H, 4.42; N, 25.31%. Found: C, 61.74; H, 4.77; N, 25.15%. Molecules 2018,23, 2310 20 o 21 4. Conclusions We ha e de eloped a me hodology o accessing bis(1,2,3- iazole) unc ionalized quinoline-2,4-diones in which he iazole he e ocycles a e p esen in subs i uen s a posi ions 1 and 3 o he quinoline sca old. P elimina y in es iga ion has e ealed ha hese compounds a e po en ial mul iden a e ligands o a ene- u henium. Supplemen a y Ma e ials: The ollowing a e a ailable online: 1 H NMR and 13 C NMR spec a o all new compounds. Au ho Con ibu ions: D.M. pe o med he expe imen s. The manusc ip was p epa ed h ough he con ibu ions o R.K., M.G., D.U., S.K., and J.K. Funding: The au ho s acknowledge he inancial suppo om (in e nal g an s No. IGA/FT/2018/007, unded om he esou ces o speci ic uni e si y esea ch) and he Slo enian Resea ch Agency (Resea ch Co e Funding G an P1-0230, P ojec J1-8147, and P ojec J1-9166). Acknowledgmen s: Te eza Dos álo áand Lo o Ko nik pa icipa ed in his s udy in hei unde g adua e p ojec s. 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