Application of Phosphine-Phosphite Ligands in the Iridium Catalyzed Enantioselective Hydrogenation of 2-Methylquinoline

Molecules 2010, 15, 7732-7741; doi:10.3390/molecules15117732 molecules ISSN 1420-3049 www.mdpi.com/jou nal/molecules Communica ion Applica ion o Phosphine-Phosphi e Ligands in he I idium Ca alyzed Enan ioselec i e Hyd ogena ion o 2-Me hylquinoline Miguel Rubio and An onio Pizzano * Ins i u o de In es igaciones Químicas, Consejo Supe io de In es igaciones Cien í icas and Uni e sidad de Se illa, A da. Amé ico Vespucio 49, 41092 Se illa, Spain * Au ho o whom co espondence should be add essed; E-Mail: piz[email p o ec ed]; Tel.: +34-954-489-556; Fax: +34-954-460-565. Recei ed: 6 Oc obe 2010; in e ised o m: 26 Oc obe 2010 / Accep ed: 28 Oc obe 2010 / Published: 29 Oc obe 2010 Abs ac : The hyd ogena ion o 2-me hylquinoline wi h I ca alys s based on chi al phosphine-phosphi es has been in es iga ed. I has been obse ed ha he eac ion is e y sensi i e o he na u e o he ligand. Op imiza ion o he ca alys , allowed by he highly modula s uc u e o hese phosphine-phosphi es, has imp o ed he enan ioselec i i y o he eac ion up o 73% ee. The in luence o addi i es in his eac ion has also been in es iga ed. Con a y o he bene icial in luence obse ed in ela ed ca aly ic sys ems, iodine has a dele e ious e ec in he p esen case. O he wise, a yl phospho ic acids p oduce a posi i e impac on ca alys ac i i y wi hou a dec ease on enan ioselec i i y. Keywo ds: asymme ic hyd ogena ion; chi al ligands; phosphines; phosphi es; i idium; quinolines 1. In oduc ion The use o wo coo dina ing unc ions o di e en na u e in a chi al ligand cons i u es as a e y powe ul app oach in he ield o asymme ic hyd ogena ion [1]. Thus, excellen ca alys pe o mance has been achie ed in a ple ho a o eac ions by he use o ligands which app op ia ely combine di e se C, N, S and P dono g oups [2-5]. The ca aly ic asymme ic hyd ogena ion o quinolines o p oduce op ically ac i e e ahyd o- quinolines is a e y in e es ing eac ion due o he impo ance o he esul ing p oduc s. Fo ins ance, chi al e ahyd oquinolines a e ubiqui ous p oduc s in Na u e (Figu e 1) which exhibi , in addi ion, a OPEN ACCESS Molecules 2010, 15 7733 wide ange o biological p ope ies o in e es o he pha maceu ical indus y [6-12]. A a ie y o ca aly ic sys ems, mos ly based on I complexes and chi al chela ing ligands wi h ei he equi alen (C 2 symme ic) o non equi alen (C 1 symmme ic) coo dina ing unc ions, ha e p o ided sa is ac o y esul s o his ans o ma ion. In his ega d, Zhou e al. ha e desc ibed a ca aly ic sys em o [I Cl(cod)] 2 , MeO-Biphep and I 2 ha hyd ogena es a a ie y o subs i u ed quinolines wi h high enan ioselec i i ies [13]. Likewise, Chan e al. ha e success ully applied o he diphosphines such as P-phos and Di luo phos in his eac ion [14-15]. In e es ingly, his ans o ma ion can also be e ec i ely ca alyzed by species based on less dono diphosphoni es, as shown by Ree z e al. [16]. Mo eo e , C 1 symme ic phosphine-oxazoline, phosphine-sul oximine o phosphine-phospho amidi e ligands ha e also led o e icien ca alys s [17-19]. In addi ion, complexes based on a combina ion o a monoden a e chi al phospho amidi e and an achi al phosphine, which p o ide good le els o ac i i y and enan ioselec i i y, ha e been desc ibed by Fe inga e al. [20]. Despi e he excellen esul s ob ained in hese p eceden s, he knowledge abou his eac ion is s ill limi ed. Then, s udies aimed o unde s and he in luence o impo an ea u es like ligand basici y, bi e angle o he in luence o addi i es a e highly in e es ing [13-21]. Figu e 1. Some na u ally occu ing chi al e ahyd oquinolines. N Me N Me O ON Me OMe OMe Angus u eine Galipinine Cuspa eine Among chela ing ligands wi h unequal coo dina ing g oups, we ha e ocused on phosphine- phosphi es (P-OP) and hei applica ion in asymme ic ca aly ic hyd ogena ion eac ions. In e es ingly, he dissimila elec onic p ope ies o hei P unc ionali ies p o ides an e icien di e en ia ion be ween coo dina ion posi ions, which educes he numbe o eac ion in e media es and allows a be e s e eocon ol [22-23]. Mo eo e , he highly modula s uc u e o he P-OP de i a i es de eloped in ou labo a o y (Figu e 2), enables a de ailed ca alys sc eening co e ing he in luence o phosphine, phosphi e and backbone agmen s. This app oach has success ully been applied in he Rh ca alyzed enan ioselec i e hyd ogena ion o se e al ypes o ole ins [24-26]. In addi ion, we ha e demons a ed he use ulness o P-OP ligands in he I ca alyzed hyd ogena ion o N-a yl imines [27]. As an ex ension o he scope o chi al phosphine-phosphi es in he hyd ogena ion o C=N bonds, we desc ibe he ein p elimina y esul s abou he applica ion o hese ligands in he I ca alyzed asymme ic hyd ogena ion o 2-me hylquinoline. Figu e 2. Gene al s uc u e o P-OP ligands. O P PO O R' R' R R O P PO O R' R' R R R = alkyl, a yl R' = H, Bu Molecules 2010, 15 7734 2. Resul s and Discussion In a i s s age, we ha e ca ied ou a se o eac ions o sea ch o app op ia e condi ions o he ca aly ic hyd ogena ion o 2-me hylquinoline (Eq 1). Thus, unde 40 ba o hyd ogen p essu e and a oom empe a u e, he ca alys gene a ed om [I (Cl)(COD)] 2 and ligand (S)-1a (Figu e 3), p oduced only a mode a e con e sion and a low enan ioselec i i y (en y 1, Table 1). In e es ingly, he p esence o a mo e dona ing phosphine g oup in (S)-1b led o an impo an inc ease in ca alys ac i i y, wi h a sligh imp o emen on enan ioselec i i y (en y 2). Mo eo e , a ca ionic ca alys p ecu so based on (S)-1b gene a ed a poo e ca alys (en y 3). In e es ingly, he neu al ca alys s p oduced an inc eased con e sion a a lowe p essu e bu again wi h low selec i i ies (en ies 4, 5). F om his p elimina y sc eening, condi ions o he la e eac ions we e chosen o analyze he in luence o ligand s uc u e on enan ioselec i i y (Table 2). Figu e 3. P-OP ligands used in he p esen s udy. N H 2 [I (Cl)(COD)] 2 + P-OP N H (1) O P PO O Bu Bu R R O P PO O R R R = Ph [(S)-1a], P i [(S)-1b]R = P i [(R)-2b)], Bu [(R)-2c], 2-MeC 6 H 4 [(R)-2d], 1-naph hyl [(R)-2e] O P PO O Bu Bu Ph Ph (S)-4a O P PO O Ph Ph (R)-5a O P PO O R R R = Ph [(S)-6a], P i [(S)-6b] O P PO O Bu Bu Ph Ph (S)-3a A compa ison o he ca alys pe o mance along he se ies o ligands allows one o ex ac some in e es ing obse a ions. Mos ema kably, he use o less hinde ed phosphi e g oups has a posi i e e ec on he eac ion. Thus, ca alys p epa ed wi h ligand (R)-2b p oduced an impo an inc ease on enan ioselec i i y o e (S)-1b, om 16 o 62% ee, while main aining a good con e sion (en ies 2, 3). Fu he examina ion o di e en phosphine g oups did no allow us o imp o e he alues achie ed by (R)-2b (en ies 4-6). As an al e na i e, we conside ed ligands based on e hane b idged examples, as his backbone has a posi i e e ec in he hyd ogena ion o N-a yl imines [27]. Con a y o ou expec a ions, he enan ioselec i i ies wi h hese ligands we e a he low (en ies 7-9). In an a emp o Molecules 2010, 15 7735 inc ease he p ac ical u ili y o he p esen sys em we ha e also analyzed he pe o mance o BINOL based ligands (S)-6a [28] and (S)-6b. These compounds a e s uc u ally simila o 2, bu conside ably easie o syn hesize, as he equi ed chlo ophosphi e can be p epa ed in one s ep om comme cially a ailable BINOL [29]. New (S)-6b was eadily p epa ed by condensa ion be ween 2-hyd oxyphenyl- diisop opyl phosphine and BINOL chlo ophosphi e (see Expe imen al). Table 1. Ca aly ic asymme ic hyd ogena ion o 2-me hylquinoline wi h P-OP ligands. 1 En y Ca . P ecu so P/a m %Con % ee Con 1 ½ [I (Cl)(COD)] 2 + (S)-1a 40 48 7 S 2 ½ [I (Cl)(COD)] 2 + (S)-1b 40 84 27 S 3 [I (COD)(1b)]BF 4 40 9 6 n.d. 4 ½ [I (Cl)(COD)] 2 + (S)-1a 20 72 0 - 5 ½ [I (Cl)(COD)] 2 + (S)-1b 20 96 16 S 1 Reac ions we e ca ied ou a oom empe a u e in oluene a a S/C = 100 and 0.6 M subs a e concen a ion. Ca alys p ecu so was gene a ed om [I (Cl)(COD)] 2 and P-OP ligand a a I :P-OP =1:1.1 a io unless o he wise s a ed. Con e sion was de e mined by 1 H-NMR and enan iome ic excess (ee) by chi al HPLC. Con igu a ion was de e mined by compa ison o op ical o a ion o he li e a u e alue. Table 2. Ca aly ic asymme ic hyd ogena ion o 2-me hylquinoline wi h P-OP ligands. 1 En y Ligand P/a m %Con % ee Con 1 (S)-1a 20 72 0 - 2 (S)-1b 20 96 16 S 3 (R)-2b 20 88 62 S 4 2 (R)-2c 20 7 56 S 5 2 (R)-2d 20 30 46 S 6 (R)-2e 20 34 20 S 7 (S)-3a 20 98 9 S 8 (S)-4a 20 100 0 - 9 2 (R)-5a 20 6 10 S 10 (S)-6a 20 28 45 R 11 (S)-6b 20 82 65 R 12 (S)-6b 40 63 73 R 13 (S)-6b 10 40 63 R 1 Reac ions we e ca ied ou a oom empe a u e in oluene a a S/C = 100 and 0.6 M subs a e concen a ion unless o he wise s a ed. Ca alys p ecu so was gene a ed om [I (Cl)(COD)] 2 and P-OP ligand a a I :P-OP =1:1.1 a io. Con e sion was de e mined by 1 H-NMR and enan iome ic excess (ee) by chi al HPLC. Con igu a ion was de e mined by compa ison o op ical o a ion o he li e a u e alue. 2 0.2 M subs a e concen a ion. Mos ema kably, (S)-6b led o simila esul s as hose ob ained wi h (R)-2b. On he o he hand, (S)-6a p oduced a mode a e enan ioselec i i y, bu lowe han he i P de i a i e. As shown by ligands 1, a mo e elec on dona ing ligand leads o a mo e ac i e ca alys . Finally, examina ion o ca alys based on (S)-6b a di e en p essu es exhibi ed an inc ease in enan ioselec i i y up o a 73% ee a 40 a m, bu a lowe alue a 10 a m (en ies 12, 13). In e es ingly, p oduc con igu a ion depends on he na u e Molecules 2010, 15 7736 o he phosphi e agmen . Thus, he S p oduc is a ou ed by ligands wi h a e -bu yl-subs i u ed S phosphi e g oup. On he con a y, ligands wi h an unsubs i u ed S phosphi e agmen (e.g., (S)-6a) and (S)-6b), gi e p edominan ly he R amine. As men ioned, he p esen hyd ogena ion is e y sensi i e o he p esence o addi i es. In pa icula , excellen esul s ha e been epo ed in he li e a u e by he use o iodine as coca alys [13-17]. Based on hese p eceden s we p epa ed a se o eac ions using di e en ligands in he p esence o I 2 (Table 3). As obse ed be o e, he coca alys p oduces an impo an inc ease in eac i i y, leading o eac ion comple ion in all cases. No ewo hily, he p esence o iodine p oduces a e e sal o p oduc con igu a ion in eac ions pe o med wi h ligands 1. Howe e , he enan ioselec i i ies we e decep i ely low in all cases. P esumably, coo dina ion o π-acidic phosphi e agmen in he I (III) species gene a ed by iodine addi ion [30], should no be a ou ed, which may e ode he chi al induc ion exe ed by he P-OP ligand. Table 3. Hyd ogena ion o 2-me hylquinoline in p esence o iodine. 1 En y Ligand P/a m %Con % ee Con 1 (S)-1a 40 100 30 R 2 (S)-1a 20 100 16 R 3 (S)-1b 20 100 7 R 4 (S)-3a 20 100 0 - 5 (S)-4a 20 100 11 R 6 (S)-6b 40 100 0 - 7 (S)-6b 20 100 5 R 1 Reac ions we e ca ied ou a oom empe a u e in oluene a a S/C = 100 and 0.6 M subs a e concen a ion. Ca alys p ecu so was gene a ed om [I (Cl)(COD)] 2 , P-OP ligand and I 2 a a I :P-OP:I 2 =1:1.1:10 a io. Con e sion was de e mined by 1 H NMR and enan iome ic excess (ee) by chi al HPLC. Con igu a ion was de e mined by compa ison o op ical o a ion o he li e a u e alue. In o de o imp o e he pe o mance o ca alys based on (S)-6b, we ha e nex s udied he in luence o o he addi i es men ioned in he li e a u e (Table 4). Se e al sal s we e es ed i s , al hough hey did no p o ide a bene icial e ec o e he e e ence sys em (en ies 1-5). On he con a y, an in e es ing e ec is p o ided by phospho ic acids [31-33]. Thus, diphenylphospho ic acid p oduced a mo e ac i e ca alys , al hough less enan ioselec i e (en y 6). F om his esul and he epo ed asymme ic educ ion o quinolines ca alyzed by binaph hol based phospho ic acids [34], we ha e es ed he wo enan iome s o 1,1’-binaph hyl-2,2’-diylphospho ic acid (BINOL-PO 2 H, en ies 7, 8). In e es ingly, hese acids also ha e a bene icial e ec on ca alys eac i i y and main ain he enan ioselec i i y. Howe e , hey did no show any in luence o he con igu a ion o he acid on enan ioselec i i y. P obably, mo e elabo a ed binaph hyl agmen s, including a oma ic g oups in 3,3’ posi ions, a e needed o p o ide a syne gis ic e ec o imp o e he ca aly ic sys em [35]. Molecules 2010, 15 7737 Table 4. In luence o di e se addi i es in he hyd ogena ion o 2-me hylquinoline wi h ligand (S)-6b. 1 En y Addi i e P/a m %Con % ee Con 1 none 20 82 65 R 2 pipe idine·HCl 20 19 66 R 3 Bu 4 NI 20 63 62 R 4 KCl 20 80 36 R 5 NaBF 4 20 69 49 R 6 (PhO) 2 PO 2 H 20 92 49 R 7 (R)-BINOL-PO 2 H 20 89 70 R 8 (S)-BINOL-PO 2 H 20 92 67 R 1 Reac ions we e ca ied ou a oom empe a u e in oluene a a S/C = 100 and 0.6 M subs a e concen a ion. Ca alys p ecu so was gene a ed om [I (Cl)(COD)] 2 , ligand 6b and addi i e a a I :6b:addi i e =1:1.1:10 a io. Con e sion was de e mined by 1 H-NMR and enan iome ic excess (ee) by chi al HPLC. Con igu a ion was de e mined by compa ison o op ical o a ion o he li e a u e alue. 3. Expe imen al 3.1. Gene al All eac ions and manipula ions we e pe o med unde ni ogen o a gon, ei he in a B aun Labmas e 100 glo ebox o using s anda d Schlenk- ype echniques. All sol en s we e dis illed unde ni ogen using he ollowing dessican s: Sodium-benzophenone-ke yl o benzene, die hyle he (E 2 O) and e ahyd o u an (THF); sodium o pe oleum e he and oluene; CaH 2 o dichlo ome hane (CH 2 Cl 2 ) and NaOMe o me hanol (MeOH). NMR spec a we e ob ained on B uke DPX-300, DRX-400 o DRX-500 spec ome e s. 31 P{ 1 H} NMR shi s we e e e enced o ex e nal 85% H 3 PO 4 , while 13 C{ 1 H} and 1 H shi s we e e e enced o he esidual signals o deu e a ed sol en s. All da a a e epo ed in ppm down ield om Me 4 Si. HPLC analyses we e pe o med by using a Wa e s 2690 Sys em. HRMS da a we e ob ained using a Jeol JMS-SX 102A mass spec ome e . Op ical o a ions we e measu ed on a Pe kin-Elme Model 341 pola ime e . (S)-2-(Diisop opylphosphino)phenyl-1,1’-binaph hyl-2,2’-diyl phosphi e [(S)-6b]. A solu ion o (S)-2,2’-bisnaph oxyphospho us chlo ide (0.35 g, 1.0 mmol) in oluene (10 mL) was added d opwise o (2-hyd oxyphenyl)diisop opyl phosphine (0.21 g, 1.0 mmol) and NE 3 (0.15 mL, 1.1 mmol) dissol ed in oluene (10 mL). The esul ing suspension was s i ed o 24 h, he mix u e il e ed and ola iles emo ed. The solid ob ained was dissol ed in oluene and passed h ough a sho pad o neu al alumina. Solu ion was e apo a ed yielding a whi e solid (0.25 g, 50%). [α] D20 = +222 (c 0.5, THF). 1 H- NMR (CDCl 3 , 500 MHz): δ 0.93 (m, 6H, 2 CH 3 , i P ), 1.08 (dd, J HP = 14 Hz, J HH = 7 Hz, 3H, CH 3 , i P ), 1.12 (dd, J HP = 14 Hz, J HH = 7 Hz, 3H, CH 3 , i P ), 2.18 (m, 2H, 2 CH, i P ), 7.12-7.22 (m, 2H, 2 H a om), 7.25-7.35 (m, 3H, 3 H a om), 7.37-7.50 (m, 5H, 5 H a om), 7.57 (d, J HH = 8.3 Hz, 1H, H a om), 7.60 (d, J HH = 8 Hz, 1H, H a om), 7.87-7.95 (m, 3H, 3 H a om), 8.00 (d, J HH = 8.6 Hz, 1H, H a om). 31 P{ 1 H} NMR (CDCl 3 , 202.4 MHz): δ -2.3 (b , P-C), 143.1 (d, P-O, J PP = 30 Hz); 13 C{ 1 H} NMR (CDCl 3 , 125.8 MHz): δ 19.5 (d, J CP = 10 Hz, Me, i P ), 19.6 (d, J CP = 10 Hz, Me, i P ), 20.0 (Me, iP ), 20.2 (Me, iP ), 23.2 (d, J CP = 13 Hz, CH, i P ), 23.3 (d, J CP = 13 Hz, CH, i P ), 120.1 (d, J CP = 11 Hz, CH Molecules 2010, 15 7738 a om), 121.9 (2 CH a om), 122.9 (C q a om), 123.8 (CH a om), 124.4 (d, J CP = 5 Hz, C q a om), 124.9 (CH a om), 125.1 (CH a om), 126.1 (CH a om), 126.3 (CH a om), 127.0 (CH a om), 127.1 (CH a om), 127.6 (d, J CP = 23 Hz, C q a om), 128.2 (CH a om), 128.3 (CH a om), 129.7 (CH a om), 130.1 (CH a om), 130.3 (CH a om), 131.2 (C q a om), 131.6 (C q a om), 132.6 (C q a om), 132.9 (C q a om), 135.0 (d, J CP = 7 Hz, CH a om), 147.2 (C q a om), 148.0 (d, J CP = 4 Hz, C q a om), 155.7 (dd, J CP = 14, 6 Hz, C q a om); HRMS (FAB): m/z 525, 1766, [M+H] + (exac mass calcula ed o C 32 H 31 O 3 P 2 : 525.1748). 3.2. Gene al Hyd ogena ion P ocedu e In a glo ebox, o a 2 mL glass ial was added 2-me hylquinoline (0.3 mmol), he app op ia e phosphine-phosphi e ligand (3.15 µmol), [I Cl(COD)] 2 (1.5 µmol) and he addi i e (30 µmol) in oluene (0.5 mL). Vials we e placed in a model HEL CAT18 p essu e eac o ha holds up o eigh een eac ions. The eac o was pu ged h ee imes wi h H 2 and inally p essu ized. A e 24 h, he eac o was slowly dep essu ized, solu ions we e e apo a ed and con e sions we e de e mined by 1 H-NMR. The esul ing mix u es we e dissol ed in a 95:5 n-hexane/isop opanol mix u e and il e ed h ough a sho pad o silica o emo e he ca alys . Enan iome ic excesses o 2-me hyl-1,2,3,4- e ahyd oquinoline we e analyzed by chi al HPLC (Chi acel OJ-H, low 0.5 mL/min, n- hexane:isop opanol 95:5). 4. Conclusions We ha e epo ed a p elimina y s udy abou he I ca alyzed hyd ogena ion o 2-me hylquinoline wi h phosphine-phosphi e ligands 1-6. The sc eening indica es an impo an in luence o he ligand s uc u e and has led o a con enien ca aly ic addi i e- ee sys em which achie es a good con e sion and an enan ioselec i i y o up o 73% ee. Complemen a y s udies on he in luence o addi i es indica es a dele o ious e ec o iodine. On he con a y, phospho ic acids ha e a posi i e in luence on ca alys eac i i y, wi hou a ec ing enan ioselec i i y in he case o binaph hyl phospho ic acids. S udies o deep in o hese obse a ions o he imp o emen o his ca aly ic sys em a e cu en ly unde in es iga ion. Acknowledgemen s We g a e ully acknowledge MICINN (CTQ2009-11867 and CONSOLIDER-INGENIO, CSD2007- 00006, FEDER suppo ) and Jun a de Andalucía (2008/ FQM-3830). M. R. also hanks CSIC o a JAE pos doc o al con ac . Re e ences 1. Tang, W.; Zhang, X. New chi al phospho us ligands o asymme ic hyd ogena ion. Chem. Re . 2003, 103, 3029-3070. 2. Bell, S.; Wus enbe g, B.; Kaise , S.; Menges, F.; Ne sche , T.; P al z, A. 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Sample A ailabili y: Samples o he compounds a e a ailable om he au ho s.