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1 Title Investigtion of itive effets in enntioseletive opper-tlyse C- H insertion n romti ition retions of α-izoronyl ompouns Author(s) Slttery, Ctherine.; Clrke, Leslie-Ann; 'eill, Shne T.; Ring, Aoife; For, Aln; Mguire, Anit R. Pulition te riginl ittion Type of pulition Link to pulisher's version Rights Slttery, C.., Clrke, L. A., 'eill, S., Ring, A., For, A. n Mguire, A. R. (2012) 'Investigtion of itive effets in enntioseletive opper-tlyse C-H insertion n romti ition retions of α-izoronyl ompouns', Synlett, 23(5), pp DI: /s Artile (peer-reviewe) Aess to the full text of the pulishe version my require susription. Georg Thieme Verlg Stuttgrt ew York Item ownloe from Downloe on T09:14:59Z

2 1 SYLETT: LETTER Investigtion of Aitive Effets in Enntioseletive Copper-Ctlyse C H Insertion n Aromti Aition Retions of α-dizoronyl Compouns. Ctherine. Slttery, Leslie-Ann Clrke, Shne eill, Aoife Ring, Aln For n Anit R. Mguire* Deprtment of Chemistry n Anlytil n Biologil Chemistry Reserh Fility, University College Cork, Ireln. Deprtment of Chemistry, Shool of rmy n Anlytil n Biologil Chemistry Reserh Fility, University College Cork, Ireln. Fx: +353-(0) E-mil:.mguire@u.ie Reeive: 4 ovemer 2011 Astrt: Signifint enhnements in enntioseletivities n retion effiienies in symmetri opper-tlyse C H insertion n romti ition retions of α-izoronyl ompouns in the presene of vrious group I slts re reporte. For the first time in renoi hemistry, eviene for the ritil role of the metl tion is esrie. Key wors: izoronyl, opper tlysis, C H insertion, Buhner retion, is(oxzoline) ligns, Crenoi C H insertion n romti ition retions of α-izoronyl ompouns re very importnt retions in orgni synthesis for the formtion of C C ons. 1 4 While tritionlly onute in the presene of rhoium tlysts, hirl opper systems hve lso een shown to e highly effetive tlysts for enntioseletive C H insertion 5 7 n Buhner retions. 8,9 We 7,8 n Zhou 10,11 hve reently emonstrte tht the ition of BARF {BARF = tetrkis[3,5-is (trifluoromethyl)phenyl] orte} to the tlyti omplex omprising opper soure n is(oxzoline) lign results in enhne retion effiienies n enntioseletivities in H insertion retions. However, to te the mehnisti role of BARF in renoi insertion retions hs not een isusse. Herein we report our finings on the key role of the itive in enntioseletive C H insertion n romti ition retions. Two α-izosulfones [1-izo-1-phenylsulfonyl-5- phenyl pentn-2-one 3 n methyl 2-izo-2-(4- phenylutylsulfonyl) ette 5] were hosen for this initil stuy. C H insertion retions of 3 n 5 were onute in refluxing ihloromethne in the presene of opper tlyst generte in situ from 5 mol% CuCl 2, 6 mol% is(oxzoline) lign (Figure 1) n 6 mol% itive. In generl, trnsylopentnone 4 n is-thiopyrn 6 were the mjor prouts for the insertion retions of 3 n 5, respetively. As ws oserve in our previous stuy exmining CuCl- tlyse retions, 7 C H insertion of α-izoβ-keto sulfone 3 in the presene of CuCl 2 n is(oxzoline) lign ws seen to result in very low levels of enntioseletivity (Tle 1, entry 1). Aition of BARF to the tlyti mixture ws foun to result in rmti inrese in enntioontrol (Tle 1, entry 2), n this high level of symmetri inution ws lrgely mintine for retions employing PF 6 s itive (Tle 1, entry 3). In ontrst, no signifint enhnement in enntioseletivity ws reore for retions in the presene of either B(C 6H 5) 4 or BF 4 (Tle 1, entries 4 n 5). Figure 1 Bis(oxzoline) ligns. 1 2 A slight inrese in enntioinution (91% ee) ws oserve for insertion of 3 with KBARF (Tle 1, entry 6) reltive to ylistion with BARF. otly, this result represents the highest level of symmetri inution reore to te for ylopentnone synthesis vi C H insertion. Tle 1 C H insertion retions of 1-izo-1-phenylsulfonyl-5- phenylpentn-2-one 3. 2 S 2 5 mol% CuCl 2, 6 mol% 1, 6 mol% itive 3 4 S 2 Entry Aitive Yiel (%) ee, (%) BARF PF B(C6H5) BF KBARF KPF LiPF BARF + 15-rown Isolte fter flsh hromtogrphy. Determine y hirl HPLC (see supporting informtion for etils). Asolute onfigurtion is (2R, 3R). 8 mol% 15-rown-5 e to tlyti mixture. Templte for SYLETT n SYTHESIS Thieme Stuttgrt ew York pge 1 of 4

3 2 SYLETT: LETTER Retions with the potssium n lithium slts KPF 6 n LiPF 6 resulte in erese levels of enntioseletivity reltive to retions employing PF 6 (Tle 1, entries 7 n 8 vs. 3). From the results presente in Tle 1, it is evient tht the hoie of itive hs signifint effet on the level of enntioseletivity tht n e hieve in the C H insertion retions of α-izosulfone 3. Highest enntioontrol ws hieve for retions in the presene of BARF, whih ehves s very weklyoorinting nion. 12 Retions employing less wekly oorinting nions [PF 6, B(C 6H 5) 4, BF 4 ] resulte in erese levels of symmetri inution. Thus, s erese nion oorintion ppers to orrelte to n inrese in enntioseletivity, it is prole tht the min role of these itives is to provie nke lkli metl tion in solution whih my ply key role in permitting formtion of highly effiient tlyti omplex. It is envisione tht the role of the metl tion is to effet omplete or prtil hlorie strtion from the opper omplex, therey ltering the tive tlyst speies. Eviene for this inlues isoltion of smll mounts of soium hlorie whih preipitte from the retion mixture. 16 More signifintly, when retions were onute in the presene of BARF n the rown ether 15-rown-5, whih is known to effetively omplex soium tions, the enntioseletivity ereses sustntilly, reversing the enhnement previously seen for ition of the itive speies (Tle 1, entry 9 vs. 2). Tle 2 C H insertion retions of methyl 2-izo-2-(4- phenylutylsulfonyl)ette 5. S 2 C 2 Me 5 mol% CuCl 2, 6 mol% 2, 6 mol% itive S 5 6 Entry Aitive Yiel (%) ee, (%) BARF PF B(C6H5)4 4 5 BF KBARF KPF LiPF Isolte fter flsh hromtogrphy. Determine y hirl HPLC (see supporting informtion for etils). Asolute onfigurtion is (2S, 3S). ot etermine. C 2 Me Insertion retions with methyl 2-izo-2-(4- phenylutylsulfonyl)ette 5 were lso onute (Tle 2). Although in this se the enntioseletivity hieve for ylistion in the sene of itives (Tle 2, entry 1) is muh higher thn the orresponing insertion with α-izosulfone 3 (Tle 1, entry 1), enhnement of symmetri inution is still possile for retions employing BARF, KBARF n PF 6 (Tle 2, entries 2, 3 n 6). In this instne, high levels of enntioontrol were oserve for insertions in the presene of KPF 6 n BF 4 (Tle 2, entries 5 n 7). This oservtion is in ontrst with results reore for insertion with α- izo-β-keto sulfone 3 in whih erese in ee ws note for insertion in the presene of KPF 6 n BF 4 (Tle 1, entry 5 n 7). As ws previously note for ylistion of 3, reue enntioseletivity ws oserve for insertion employing LiPF 6 (Tle 2, entry 8). Suprisingly, use of B(C 6H 5) 4 s itive resulte in the formtion of very little C-H insertion prout, with severl ompeting sie retions inste oserve (Tle 2, entry 4). Enhnement of enntioseletivity in the presene of BARF hs lso een oserve in opper-tlyse Buhner retions of α-izoketones. 8 As summrise in Tle 3, ltertion of the ounterion hs signifint effet on symmetri inution in the intrmoleulr romti ition retions of izoketones 7 n 7. In the sene of the soium tion, little or no enntioseletivity is hieve using CuCl n is(oxzoline) lign 1 (Tle 3, entries 1 n 7), while ition of BARF, KBARF or PF 6 to the tlyti mixture results in goo enntioseletivity in eh se (Tle 3, entries 2 4 n 8 10). As ws previously oserve for the C H Tle 3 Buhner retion of izoketones 7 n 7. 7 : = H : = Cl 2 5 mol% CuCl, 6 mol% 2, 6 mol% itive, Entry Aitive Yiel (%) ee (%) 1 H H BARF H PF H KBARF H LiPF H BARF + 15-rown Cl Cl BARF Cl PF Cl KBARF Cl LiPF Cl BARF + 15-rown Isolte fter flsh hromtogrphy. Determine y hirl shift 1 H MR experiments using (+)- Eu(Hf)3. Previously pulishe results. 8 8 mol% 15-rown-5 e to tlyti mixture. 8 Templte for SYLETT n SYTHESIS Thieme Stuttgrt ew York pge 2 of 4

4 3 SYLETT: LETTER insertion retions of 3, use of LiPF 6 s n itive is less effetive thn PF 6 in filitting highly enntioseletive retions (Tle 3, entries 5 n 11). ne gin, ition of 15-rown-5, together with BARF, (Tle 3, entries 6 n 12) resulte in sustntil erese in symmetri inution in line with results reporte for C-H insertion of α- izosulfone 3. In onlusion, we hve emonstrte for the first time the key role of the lkli metl tion in prouing highly enntioenrihe prouts vi C H insertion n romti ition of α-izoronyl ompouns. Work is urrently unerwy to further investigte the influene of itives in opper-tlyse renoi trnsformtions. Supporting Informtion for this rtile is ville online t Aknowlegment Finnil support from the Irish Reserh Counil for Siene, Engineering n Tehnology, Progrmme for Reserh in Thir Level Institutions Cyle 4 n Eli Lilly is grtefully knowlege. Referenes (1) Slttery, C..; For, A.; Mguire, A. R. Tetrheron, 2010, 66, (2) Doyle, M. P.; MKervey, M. A.; Ye, T. Moern Ctlyti Methos for rgni Synthesis with Dizo Compouns, Wiley-Intersiene: ew York, (3) Doyle, M. P.; Duffy, R.; Rtnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (4) Dvies, H. M. L.; Bekwith, R. E. J. Chem. Rev. 2003, 103, (5) Flynn, C. J.; Elote, C. J.; Lwrene, S. E.; Mguire, A. R. J. Am. Chem. So., 2010, 132, (6) Frile, J. M.; Gri, J. I.; Myorl, J. A.; Roln, M. rg. Lett., 2007, 9, 731. (7) Slttery, C..; Mguire, A. R. rg. Biomol. Chem. 2011, 9, 667. (8) eill, S.; Keeffe, S.; Hrrington, F.; Mguire, A. R. Synlett, 2009, (9) Keeffe, S.; Hrrington, F.; Mguire, A. R. Synlett, 2007, (10) Liu, B.; Zhu, S.-F.; Zhng, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem. So. 2007, 129, (11) Chen, C.; Zhu, S.-F.; Liu, B.; Wng, L.-., Zhou, Q.-L. J. Am. Chem. So. 2007, 129, (12) Krossing, I.; Re, I. Angew. Chem. Int. E. 2004, 43, (13) Zhu, S.-F.; ie, J.-B.; Zhng, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. So. 2006, 128, (14) Rosenerg, M. L.; Vlšná, K.; Gupt,. S.; Wrgg, D.; Tilset, M. J. rg. Chem. 2011, 76, (15) Krumper, J. R.; Gerish, M.; Suh, J. M.; Bergmn, R. G.; Tilley, T. D. J. rg. Chem. 2003, 68, (16) Presene of Cl onfirme y PRD nlysis (see supporting informtion for etils). Templte for SYLETT n SYTHESIS Thieme Stuttgrt ew York pge 3 of 4

5 4 SYLETT: LETTER Templte for SYLETT n SYTHESIS Thieme Stuttgrt ew York pge 4 of 4