Catalyzed Hydroamination Reactions Lutz Ackermann Georg-August-Universität Göttingen

Transcription

1 Catalyzed ydroamination eactions Lutz Ackermann Georg-August-Universität Göttingen

2 Overview Introduction ydroamination of Alkynes 1 Activation of the Amine 2 Activation of the Alkyne ydroamination of Alkenes 1 Activation of the Amine 2 Activation of the Alkene

3 1 Literature eview Articles: General reviews: - Brunet, J. J.; eibecker, D. In Catalytic eterofunctionalization; Togni, A., Grützmacher,., Eds.; Wiley-VC: Weinheim, 2001; pp Beller, M.; Seayad, J.; Tillack, A.; Jiao,. Angew. Chem., Int. Ed. 2004, 43, Müller, T. E.; ultzsch, K. C.; Yus, M; Foubelo, F.; Tada, M. Chem. ev. 2008, 108,

4 1 Why ydroamination? Amines, imines and enamines are - important bulk and fine chemicals - biologically active compounds - versatile synthetic intermediates O O latonin (tissue hormone) O Verapamil (cardiac drug) O CO 2 Tromaril (anti-inflammatory)

5 1 Atom-Efficient Alternative

6 1 ydroamination of Alkenes, Alkynes, and Allenes

7 1 egioselectivity

8 1 Obstacles - Addition of 3 or simple amines to unactivated alkenes is feasible slightly exothermic or approximately thermoneutral, e.g C C 2 Δ = kj/mol, ΔS = J/mol, ΔG = kj/mol Steinborn, D.; Taube,. Z. Chem. 1986, 26, Attack of the amine nitrogen on electron-rich (non-activated) multiple bonds leads to electrostatic repulsion. high activation barrier - Concerted [2+2] addition of the bond to the alkene is orbital-symmetry forbidden - Intermolecular hydroamination reactions: negative reaction entropy ΔS

9 1 Uncatalyzed Addition eactions: Conjugate Addition Uncatalyzed direct nucleophilic addition of amines proceeds easily only with electron-deficient (activated) C C multiple bonds (aza-michael addition, conjugate addition). EWG EWG EWG EWG EWG = C(O), CO 2, C, S(O), O 2,... for the hydroamination of electronically unactivated C C multiple bonds, catalysts are mandatory!

10 1 chanistic Considerations Activation of the Amine ydroamination of alkynes

11 1 chanistic Considerations Activation of the Amine ydroamination of alkenes

12 1 chanistic Considerations Activation of the C-C Multiple Bond Activation of alkynes

13 2 ydroamination eactions of Alkynes 2.1 Activation of the Amine

14 2.1 Alkali tals - Efficient Catalyst + KO (18 mol %) decaline, C eppe, W.; Keyssner, E. (I. G. Farbenindustrie AG) DE618120, 1935.

15 2.1 Lanthanide-Based Catalysts Ph + 2 Pr 2 Si(C 5 4 ) 2 dc(tms) 2 (1.3 mol %) C 6 D 6, 60 C Ph Pr 85 % Li, Y.; Marks, T. J. Organometallics 1996, 15, activation of the amine regioselective intra- and intermolecular hydroamination reactions primary and secondary amines relatively mild reaction conditions rigorously anhydrous/anaerobic reaction conditions

16 2.1 Lanthanide Complexes as Catalysts Amido-chanism 1 [Ln] [Ln] [Ln] 2 1 [Ln] 1 2

17 2.1 Titanium Catalysts Intermolecular eactions SiO 2 O Cp 2 Ti 2 (3.0 mol %) Ph Ph + Ph 2 Ph, 100 C Ph Ph Ph 92 % LiAl 4 Ph Ph Ph 62 % Ph Ph Angew. Chem., Int. Ed. 1999, 38, restricted to primary amines

18 2.1 Catalyst Preparation Ph + Ph 2 [Ti] (3-10 mol %) Ph, C Ph Ph > 92 % Ti Cl Cl + 2 Li - 2 LiCl Ti 48 / 25 g TiCl Li 2-4 LiCl Ti( 2 ) 4 2 / 25 g 576 / 25 g side-product formation (LiCl) strong bases mediate hydroamination themselves

19 2.1 TiCl 4 as Precatalyst - Scope TiCl 4 (10-20 mol%), tbu Ph, 105 C strong external base is not required for catalyst preparation Organometallics 2003, 22,

20 2.1 Group IV-Transition tal Catalysts - chanism 1 1 Cp 2 M( 1 ) Cp 2 M 1 M = Zr, Ti (, U) imido complex catalytically competent formal [2+2] cycloaddition protonolysis rate-limiting step 1 1 [M] Cp 2 M Zr, Ti: Bergman,. G. et al. J. Am. Chem. Soc. 1992, 114, ; J. Am. Chem. Soc. 2001, 123, U: Eisen, M. S. et al. Organometallics 2001, 20,

21 2 ydroamination eactions of Alkynes 2.2 Activation of the Alkyne

22 2.2 rcury-based Catalyst n-pent + go (4-12 mol %) 2 Ph BF 3 OEt 2 (3-9 mol %) C n-pent Ph C 2 = % = Et 19 % Loritsch, J. A.; Vogt,.. J. Am. Chem. Soc. 1939, 61, n-pent + PhEt gcl 2 (5 mol %) TF, 60 C, 1 h n-pent Et C 3 Ph + n-pent Et C 2 Ph 84 % >95 < 5 Barluenga, J; Aznar, F.; Liz,.; odes,. J. Chem. Soc., Perkin Trans , primary and secondary amines high toxicity of catalysts

23 2.2 Thallium-Based Catalyst Ph + 2 Ph Tl(OAc) 3 (2 mol %) no solvent, 60 C, 7 h Ph C 3 Ph 57 % Ph + Ph Tl(OAc) 3 (2 mol %) no solvent, 60 C, 7 h Ph C 2 Ph 31 % Barluenga, J; Aznar, F. Synthesis 1977, 195. primary and secondary amines high toxicity of catalysts

24 2.2 Gold-Based Catalyst Intermolecular ydroamination 2 aaucl O (5 mol %) C, reflux, 1h ex 80 % ex Fukuda, Y.; Utimoto, K.; ozaki,. eterocycles 1987, 25, (PPh 3 )Au (0.1 mol %) Ph + Br 3 PW 12 O 40 (0.5 mol %) no solvent, 70 C, 2 h Ph C 3 94 % Br Mizushima, E.; ayashi, T.; Tanaka, M. Org. Lett. 2003, 5, highly efficient terminal and internal alkynes primary aniline derivatives, no alkyl amines Markovnikov selectivity

25 2.2 Au-Catalyzed ydroamination Proposed chanism [Au] 2 Ar Ar coordination [Au] 1 1 Ar 2 inner-sphere C- bond formation [Au] 2 Ar 2 Mizushima, E.; ayashi, T.; Tanaka, M. Org. Lett. 2003, 5, eview: Widenhoefer,. A.; an, X. Eur. J. Org. Chem. 2006,

26 2.2 Platinum Catalyst Bu + 2 Ph PtBr 2 (0.3 mol %) no solvent, 60 C, 4 d Bu C 3 Ph 28 % Ph + 2 Ph PtBr 2 (0.3 mol %), + (0.9 mol %) no solvent, 100 C, 2 d Ph C 3 Ph 44 % relatively low catalytic activity side-products due to transfer hydrogenation (e.g. amines and quinolines) are formed terminal alkynes and primary anilines Markovnikov selectivity Brunet, J.-J. et al. J. Mol. Catal. A: Chem. 2005, 240,

27 2.2 Palladium-Based Catalyst Early Intramolecular ydroaminations O Et 2 ex Et PdCl 2 (1 mol %) 84 % C, reflux, 3h ex Utimoto, K.; Miwa,.; ozaki,. Tetrahedron Lett. 1981, 22, Bu 2 PdCl 2 (5.0 mol %) C, reflux, 1h Bu 81 % Utimoto, K.; et al. Tetrahedron Lett. 1988, 29,

28 2 ydroamination of Alkynes - Summary 3 catalyst Alkynes are usually less easily accessible when compared to alkenes Through activation of amines: - Alkali tals, Ln, An, early TM (Ti, Zr) - Oxidative addition with late TM (u) - anti-markovnikov selectivity can be achieved Through activation of alkynes: - Traditionally with g, Tl (highly toxic) - Late transition metals (Au, Pd, h, Pt, ) - Usually provide Markovnikov selectivity with good functional group tolerance

29 3 ydroamination eactions of Alkenes 3.1 Activation of the Amine

30 3.1 Base-Catalysis Early Examples - base-catalyzed hydroamination reactions + M' + 2 M 2 M - ' M 2 e.g. Li, Li 2, a 2, KOt-Bu, a eview: Adv. Synth. Catal. 2002, 344, an early example: a (4 mol %) + pyridine, 100 C 28 bar 83 % owk, B. W.; Little, E. L.; Scott, S. L.; Whitman, G. M. J. Am. Chem. Soc. 1954, 76, Wollensak, J.; Closson,. D. Org. Synth. 1973, 5, => intermolecular hydroamination of unactivated olefins under relatively harsh conditions

31 3.1 Base-Catalyzed ydroamination Industrial Applications LiEt 2 (1 mol %) Et 2, 92 % Et 2 O myrcene diethylgeranylamine Takasago ( )-menthol process

32 3.1 Synthesis of Biologically Active Compounds - application to the synthesis biologically active compounds - anti-markovnikov addition to styrenes + Bn n-buli (10 mol %), TF, 65 C Bn = Cl: 38 % = : 75 % O Ar Serotonin (5-T)-receptor (schizophrenia, Parkinson s desease, depression, ) Chem. Eur. J. 2004, 10,

33 3.1 Base-Catalyzed ydroamination - chanism - mechanism 2 M'' important features: 2 M '' inexpensive catalysts, but tolerate only few functional groups 2 ' ' fast slow 2 2 M '

34 3.1 Organolanthanide as Catalyst 2 n Cp* 2 LaC(TMS) 2 (3 mol %) Ph, 60 C n n = 1: TOF = 140 h -1 n=2:tof=5h -1 Gagné, M..; Marks, T. J. J. Am. Chem. Soc. 1989, 111, Pr 2 2 Si(C 5 4 ) 2 dc(tms) 2 (20 mol %) C 6 D 6, 60 C Pr 90 %, TOF = 0.4 h -1 Li, Y.; Marks, T. J. Organometallics 1996, 15, significantly lower reactivity in intermolecular hydroaminations - Markovnikov selectivity

35 3.1 Organolanthanides as Catalysts - chanism L 2 Ln 2 L 2 Ln 2 L 2 Ln Gagné, M..; Marks, T. J. J. Am. Chem. Soc. 1989, 111, eview: ong, S.; Marks, T. J. Acc. Chem. es. 2004, 37,

36 3.1 Ti( 2 ) 4 -Catalyzed Intramolecular ydroamination Ph Ph Ti( 2 ) 4 (5 mol %) 2 Ph, 110 C, 24 h Ph Ph 92 % Org. Lett. 2005, 7, Intermolecular eactions: Angew. Chem. Int. Ed. 2005, 44, Enantioselective: Angew. Chem. Int. Ed. 2007, 46, primary amines - secondary amines are not converted - imido mechanism

37 3.1 Ti( 2 ) 4 -Catalyzed ydroamination - chanism L 2 Ti( 2 ) L 2 Ti imido complex catalytically competent formal [2+2] cycloaddition protonolysis rate-limiting step 1 L 2 Ti L 2 Ti 2 1

38 3.1 Iridium-Catalyzed ydroaminations + Ph 2 (PEt 3 ) 2 Ir(C 2 4 ) 2 Cl (10 mol %) ZnCl 2 (2 mol %), TF, reflux Ph TOF = 0.08 h -1 Milstein, D. et al. J. Am. Chem. Soc. 1988, 110, artwig, J. F. et al. Science 2005, 307, Ph 2 [(PP*)IrCl] (1-2 mol %) "F - ", 75 C (2S) Ph (2) Ph - first intermolecular asymmteric hydroamination PP* = (,S)-Josiphos, yield: 81 % 31 % 69 % PP* = (S)-BIAP, yield: 22 % 2.5 % 97.5 % Togni, A. et al. J. Am. Chem. Soc. 1997, 119,

39 3.1 Iridium-Catalyzed ydroamination - chanism Ph 2 Ph (PEt 3 ) 2 IrCl oxidative addition of aniline 2 P 2 P Ph Ir Cl x-ray (PEt 3 ) 2 Ir(Ph)()Cl J. Am. Chem. Soc. 1988, 110,

40 3 ydroamination eactions of Alkenes 3.2 Activation of the Alkene

41 3.1 Palladium-Catalyzed Intermolecular ydroamination + [Pd(PPh 3 ) 4 ] (2 mol %) Ph 2 Ph TFA (20 mol %) Ph, 100 C, 12 h 83 % artwig, J. F. et al. J. Am. Chem. Soc. 2000, 122, See also: Ozawa, F. et al. Angew. Chem. Int. Ed. 2001, 40, O [Pd(O 2 CCF 3 ) 2 ] (5 mol %) dppf (10 mol %) TFA (20 mol %) dioxane, 120 C, 24 h artwig, J. F. et al. J. Am. Chem. Soc. 2003, 125, intermolecular hydroamination (also with an alkyl)amine with Markovnikov selectivity - limited to vinylarenes - primary and secondary amines - Brønsted acid as cocatalyst - enantioselective hydroamination reported (up to 63 % ee) O 75 %

42 3.1 Palladium-Catalyzed ydroamination Ph, OTf Ph Ar, OTf L 2 Pd - illustrated for Pd (O) Ph Ph Ar L 2 Pd Ph 2 Ar OTf PdL 2 Ar 2 artwig, J. F. et al. J. Am. Chem. Soc. 2006, 128,

43 3.1 Pd-Catalyzed ydroamination: Initiation for Pd(II) 2 PdL L 2 Pd(OTf) 2 CF 3 Ph, 80 C % 2+ PdL Ar Ar + L PdL 2 Pd Ar - Ph artwig, J. F. et al. J. Am. Chem. Soc. 2002, 124, palladium hydride is relevant - η 3 -benzyl complex characterized by x-ray diffraction

44 3.2 Platinum-Catalyzed Intermolecular ydroamination 2 C PtBr2, Bu4PBr, TFA 150 C, 96 h + C 4 9 TO > % 5% Brunet, J.-J. et al. Organometallics 2004, 23, ; Organometallics 2005, 24, ; Organometallics 2006, 25, highly active - applicable simple alkyl-substituted alkenes - not air-sensitive - Markovnikov selectivity

45 3.2 Platinum-Catalyzed Intramolecular ydroamination Ph Ph Bn [PtCl 2 ( 2 C=C 2 )] 2 (2.5 mol %) PPh 3 (5.0 mol %) 1,4-dioxane, 120 C, 16 h Ph Ph Bn 75 % Wiedenhoefer,. A. et al. J. Am. Chem. Soc. 2005, 127, For less basic (sulfon)amides, see: Wiedenhoefer,. A. et al. Org. Lett. 2005, 7, ; Tilley, T. D. et al. J. Am. Chem. Soc. 2005, 127, basic secondary alkylamines can be cyclized - Less basic -nucleophiles (e.g. amides) can be added to alkenes with Au-based catalysts: e.g. e, C. et al. J. Am. Chem. Soc. 2006, 128, ; Angew. Chem., Int. Ed. 2006, 45, Wiedenhoefer,. A. et al. Org. Lett. 2006, 8, ; Angew. Chem., Int. Ed. 2006, 45, ; Chem. Commun. 2006, ; eview: Widenhoefer,. A.; an, X. Eur. J. Org. Chem. 2006,

46 3.2 Platinum-Catalyzed Intramolecular ydroamination - chanism [Pt] Bn Bn, Bn Bn [Pt] [Pt] Wiedenhoefer,. A. et al. J. Am. Chem. Soc. 2005, 127,

47 3 Alkene ydroamination Summary & Conclusion Activation of amines - Alkali metal-based catalysts: industrial processes, limited functional group tolerance - Ln-based catalysts: efficient intramolecular reactions, very sensitive - Group IV transition metal-based catalysts: intramolecular, asymmetric - Iridium-catalyzed (asymmetic) intermolecular hydroamination of strained alkenes Activation of alkenes: - Markovnikov hydroamination with Pd-, Pt- and (Au)-based catalysts (mainly intramolecular or conjugated alkenes, excetion ethylene) - anti-markovnikov hydroamination of conjugated alkenes with h- and u-based catalysts Generally applicable catalysts for intermolecular, particularly anti-markovnikov, hydroaminations of non-conjugated alkenes are highly desirable!