Baran Lab A ziridines in S y nthesis M. Jessing More S character of the lone pair which results in lower basicity and reduced Aziridines can be synthesized in numerous ways including SN2 displacement, π-donor ability. Upon ring opening aprox. 25 kcal/mol is released. 1-4 addition, addition of carbenes, electrophiles, nitrenes and reduction H Activated aziridines N R = CO2R, SO2R and COR R pKa = 8 N O NH Non-activated aziridines 2 R = H, Alkyl and Aryl N pKa = 10.98 O SO H O H The pyrimidal inversion of nitrogen in the aziridines (8-12 kcal/mol) are higher in NH2 energy than for open chained amines. Separate NMR spectras can be observed. HO H2SO4, 71% NaOH, 27% N Certain N-chloro- and N-alkoxyaziridines are chiral. EtO C 2 CO2Et NH3 N N O3SO Cl OMe H. Wenker. JACS. 1935, 2328. There has since been developed a waste arsenal of synthetic methods to make O O chiral aziridines, from chiral starting materials over chiral auxilaries to R' O R'Li Li asymmetric catalysis. R N R N R R' TsCl, i LiAlH4 S. Wattanasin and F. G. Kathawala. Tet. lett. 1984, 811. CO2H CO2H Ph DIPEA Ph ii TsCl, Et3N Ph 96% 90% NTs Unprotected amino aldehydes NH2 NHTs NH M. B. Berry and D. Craig. Synlett. 1992, 41. O NH OH i NaN3 N ii TBSCl CHO S.A.E. O HN R OH R OH iii PPh3 R OH iv TBAF R. Hili and K. Yudin. JACS. 2006, 14772. 82% D. Tanner and P. Somfai. Tet. lett. 1987, 1211. O OH + H3O NH N N R R H2O R BuLi NH NH2 AlMe3 72% O OH R. Najime, S. Pilard and M. Vaultier. Tet. lett. 1992, 5351. 1 Baran Lab A ziridines in S y nthesis M. Jessing i ArSNa Ts . ii TsNH2, BF3 OEt2 O + - N iii Me3O BF4 R1 R1 R iv NaH O R2 R2 Tol OMe 66-94% OMe S Li R CO2Me A Toshimitsu, H. Abe, C. Hirosawa and K. Tamao. J. Chem. Soc., Perkin Trans I.. 1994, 3465 N NH H Br Br OLi O N R H O SOTol O nBuLi or S Tol OH i SOCl2 O S OSO - O 64-77%, >94% de ii RuO RNH 3 LiAlH4 or 4 2 NaOH R2 O R2 R2 F.A. Davis, PZhou and G.V. Reddy. JOC. 1994, 3243. R1 R1 R1 62-89% R1 RN OH R2 NHR B. B. Lohray, Y. Gao and K. B. Sharpless. Tet. lett. 1989, 2623. HO N TsCl, R Chiral N NaBH4 NH CO2R' R CO2R' CO2R' R O NHR O O R tertiary H NR base RNH2 Base 4 H 1 H NAux* R NAux* R NAux* Br H Br 60-89%, >90% de H P. Garner, O. Dogan and S. Pillai. Tet. lett. 1994, 1653. G. Cardillo,S. Casolari, L. Gentiluca and C. Tomasini. Angew. Chem. Int. Ed. Engl. 1996, 1848. R1 O O N R1 OAc Organocatalyst N R H 54-68%, 4-10:1 dr R H H M. M. H. Verstappen, G. J. A. Ariaans and B. Zwanenburg. JACS 1996, 8491. 84-99% ee R1 = Cbz or Boc J. Vesely, I. Ibrahem, G.-L. Zhao, R. Rios and A. Córdova. Angew. Chem. Int. Ed. Engl. 2006, Early view. O N Cl StBu O O O O O Dpp O Dpp O N N Cl CN NAux* NaHMDS NAux* N 40-78%, R H OO H HCl ∆ Br R H N >95% de H 83%, >96% ee only cis J.-L. Vaerman and H. G. Viehe. Tet. 1989, 3183. NC J. B. Sweeney, A. A. Cantrill, A. B. McLaren and S. Thobhani. Tet. 2006, 3681. StBu 2 Baran Lab A ziridines in S y nthesis M. Jessing CuOTf Ph ROH O O PhI=NTs N Sn(OTf)2 or PhHN OR Chiral Ligand BF3OEt2 75%, >98% ee R1 R2 66-92% NC NC R1 R2 NH B. A. B. Prasad, G. Sekar and V. K. Singh. Tet. lett. 2000, 4677. Z. Li, K. R. Conser and E. N. Jacobsen. JACS 1993, 5326. H Bn O Bn Me Ph Ph H H Bn N MeO CCl N O N N Bn NTs 2 Me H OEt CH3CN Ph Ph 92% OEt CuOTf, PhINTs 68%, 90% ee O O T. B. Sim, S. H. Kang, K. S. Lee and W. K Lee. JOC. 2003, 104. D. Tanner, P. G. Anderson, A. Harden and P. Somfai. Tet. lett. 1994, 4631. H R2 CO Et 2 HNR2R3 R N2CHCO2Et 2 10% BiCl3 or NHR both high de and ee can N R1 N 10 % B(C6H5)3 be achived w. VAPOL N R 93-99% R1 NR2R3 K. B. Hansen, N. S. Finney and E. N. Jacobsen. Angew. Chem. Int. Ed. Engl. 1995, 1676. N. R. Swamy and Y. Venkateswarlu. Synth. Commun.. 2003, 547. J. C. Antilla, W. D. Wulff. JACS 1999, 5099. I. D. G. Watson, Ak. K. Yudin. JOC. 2003, 5160. For nonactivated aziridines ring opening is borderline between SN1 and SN2. Ph N PhHN F R1 Ph H 20% Pd(OH) /C Ph 2, 2 R Ph Ph 93-99% 1 HF .pyr R2 H H R2 H N 60% H NH2 T. Satoh, R. Matsue, T. Fujii and S. Morikawa. Tet. 2001, 3891. H T.N. Wade. JOC. 1980, 5380. PhSe OBn OBn OBn AIBN R N PhSeH R Bu3SnH N N BnO AcOH 65-96% 80-96% H 67% BnO NHAc R H HO NH OH trans 10:1 cis O OH H. Dehmlow, J. Mulzer, C. Seilz, A. R. Strecker and R. Kohlmann. Tet. lett. 1992, 3607. M. Besev and L. Engmann. Org lett. 2002 3023. 3 Baran Lab A ziridines in S y nthesis M. Jessing For activated aziridins ring opening is normally through SN2 at the least hindered R2 Pd(OAc)2 Y ring-carbon and for fused bicyclic systems via Fürst-Plattner diaxial opening PPh R1 R2 3 XCY X Br N MgBr N 34-97% R quant. CO2R' N Pd(Ph3P)2 2 H CO2R' R R1 R 1 R H NHCO2Et D. C. D. Butler, G. A. Inman and H. Alper. JOC. 2000 5887. N B. M. Trost, D. R. Fandrick. JACS. 2003 11836. NHCO2Et NaBr CO2Et CO R' Amberlyst 15 2 Co2(CO)8 R quant. CO, DMF H O Br Chrial Ti G. Richi, R. D'Achille and C. Bonini. Tet. lett. 1996, 6893. catalyst N Bn AcO 80% N Ph Ph Bn H AcOH H N NHCO2Et V. Mahadevan, Y. D. Y. L. Getzler and G. W. Coates. Angew. Chem. Int. Ed. Engl. 2002, 2781. 100% CO2Et H H. Takeuchi and K. Koyama. J. Chem. Soc. Perkin Trans 2. 1981, 121. Ph i EtMgBr ii ICH2CH2CH2I RMgBr N iii NaB(AcO) H 3 Cu(OTf)2 NHTs Pr N H 42%>95% de Chiral ligand N Ts Ph 45-89%, 0-91% ee H H R P. Muller and P. Nury. Helv. Chem. Acta. 2001, 662. J. F. Hayes, M. Shipman and HTwin. Chem Commun. 2001 1784. NH2 TFA, 0oC H H R 72% CO2Me CO2Et R CO2Me OH N O O NH2 CO Et Bu 2 S o R Me FVP Me N Tol O TFAA, 35 C N N Bu N CO2Me 350 oC, 0.05 torr 59% R OH 84% H Ph Ph CO2Me B. R. Henke, A. J. Kouklis and C. H. Heathcock. JOC. 1992, 7056. O N S O H F3C Tol H F. A. Davis and G. V. Freddy. Tet. lett. 1996, 4349. 4 Baran Lab A ziridines in S y nthesis M. Jessing O O O O Lewis Acid O O Ph microwave toluene N N N N O N N NH N Ts NH2 HN O InCl3 Ph Boc Ph O Ph O N (60:40 of regioisomers) 2 3 N 85% N Ph H H J. S. Yandav, B. V. S. Reddy, S. Abraham and G. Sabitha. Tet. lett. 2002, 1565. H R R H R1Cu(CN)M R1Cu(CN)M R R C H N N C R1 NH Mts Mts NH Mts R1 72-99% Mts H H. Ohno, A. Toda, N. Fujii, Y. Takemoto, T. Tanaka and T. Ibuka. Tet. 2000, 2811. G. Cardillo, L. Gentilucci, M. Gianotti and A. Torlomelli. Synlett. 2000, 1309. Me Me H Ts Me Ts H LDA N Me Me N N 95% BF3OEt2 N CO2tBu Ph Ph Me H Me Me Me Ph Me 96% Ph CO2tBu A. Mordini, L. Sbaragli, M. Valacchi, F. Russo and G. Reginato. Chem Commun. 2002 778. J. Åhman and P. Somfai. JACS. 1994, 9781. H OBn R R NHTs 1 TMSX 1 H LiHMDS N Ts 5% TBAF X = CN, N3, Cl Bn N 81% N O 60-99% H R2 R2 X OBn O Bn J. W. Wu, X.-L. Hou and L.-X. Dai. JOC. 2000, 1344. U. M. Lindström and P. Somfai. JACS. 1997, 8385. R2 R1 BF OEt R2 R1 R2 R1 3 2 CAN Ts Red.Al or ROH MeOH LiAlH4 or H NH TsHN OR >92% N 70-95% TsHN OMe N 2 LiMe2Cu HO OR HO OR Ts low regioselectivity NaN3 and H2O R' H can be used too B. A. B. Prasad, G. Sekar and V. K. Singh. Tet. lett. 2000, 4677. R' = Me or H S. Chandrasekhar, C. Narsihmulu and S. S. Sultanai. Tet. lett. 2002, 7361. D. Tanner. Angew. Chem. Int. Ed. Engl. 1994, 599. and ref. cited therein 5 Baran Lab A ziridines in S y nthesis M. Jessing Ts Ts SmI2, DMEA NHTs O N 2- R MeOH or THF N Te NHTs 1 O R1 R 70-98% 2 R R3 R2 X OTs (Te, NaBH4, DMF) 2 R2 74-90% X R1 R1 G.