1 Synthesis and Characterization of N-Heterocyclic Carbene Palladium(II) Complexes. The Catalytic Application on Strecker Synthesis of α- aminonitriles 學生：洪柏楷 指導教授：于淑君 博士 2010 / 05 / 17 Department of Chemistry & Biochemistry Chung Cheng University

2 Phosphine Ligand Phosphines are electronically and sterically tunable. Expensive. Air/water sensitive and thermally unstable. Metal leaching. Chemical waste - water bloom. 25 mL USD 25 G 396 USD 100 mL 31.9 USD 10G 135.5USD

3 N-Heterocyclic Carbenes NHCs are stronger σ-donor and weaker π-acceptor than the most electron rich phosphine. NHCs can be useful spectator ligands, because they are sterically and electronically tunable. NHCs can promote a wide series of catalytic reactions like phosphine. NHCs have advantages over phosphines and offer catalysts with better air-stability. [M]

4 N-Heterocyclic Carbenes as Ligands - In the early 90's NHC were found to have bonding properties similar to trialklyphosphanes and alkylphosphinates. - compatible with both high and low oxidation state metals -examples: -reaction employing NHC's as ligands: Herrmann, W. Angew. Chem. Int. Ed. 2002, 41, Herrmann, W. A.; Öfele, K; Elison, M.; Kühn, F. E.; Roesky, P. W. J. Organomet. Chem. 1994, 480, C7-C9.

C-H Activation of Methane Oxidation of Alcohols Reductive Aldol Reaction Allylation of Aldehydes Strecker Reaction 5 The Catalytic Applications of Pd(II) Heck reaction Suzuki–Miyaura Reaction Carbon-Surfur Coupling Reactions Buchwald-Hartwig Reactions Etherification Reaction Ethylene-CO copolymerization Reaction

6 Strecker Amino Acid Synthesis The Strecker amino acid synthesis is a series of chemical reactions that synthesize an amino acid from an aldehyde (or ketone). Adolph Strecker was the first to understand this organic reaction at Two novel organogallium(III) complexes were tested in vitro against human tumour. Santiago Gomez-Ruiz, Milena R. Journal of Organometallic Chemistry 2009,694, 2191–2197. Strecker, D. Ann.Chem. Pharm. 1850,75,

The Various Modes of α-Aminonitrile Reactivity 7 Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29,

8 Lewis Acid-Catalyzed Strecker Reaction Lewis acid catalysts Et 3 N 、 InCl 3 、 Ga(OTf) 3 、 BiCl 3 Paraskar, A. S.; Sudalai, A. Tetrahedron Lett. 2006, 47, Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, Surya Prakash, G. K.; Mathew, T. ; Panja, C.; Alconcel, S.; Vaghoo, H.; Do, C.; Olah, G. A. PNAS 2007, 104, De, S. K. ; Gibbs, R. A. Tetrahedron Lett. 2004, 45, Transition metal Lewis acid catalysts RuCl 3 、 NiCl 2 、 Sc(OTf) 3 、 Cu(OTf) 2 De, S. K. Synth. Commun. 2005, 35, De, S. K. J. Mol. Catal. A: Chem. 2005, 225, Lanthanide Lewis acid catalysts Pr(OTf) 3 、 La(O-i-Pr) 、 Yb(OTf) 3 De, S. K. Synth. Commun. 2005, 35, Others KSF 、 I 2 Yadav, J. S.; Subba Reddy, B. V.; Eeshwaraiah B.; Srinivas, M. Tetrahedron 2004, 60, Royer, L.; De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46,

9 Motivation Using NHCs ligand to replace phosphine ligand in organomatallic catalysis. Synthesis of NHC-Pd(II) complexes with well-defined structures. Developing a practical and effective process for the Strecker Reaction. Greener catalysis –solventless and microwave conditions.

10 Toshikazu Hirao, Kenji Tsubata. Tetrahedron Letters 1978, 18, The First Palladium(II) Carbene Complexes

11 Lijin Xu, Weiping, Chen, Journal of Organometallic Chemistry, 2000, 598, 409–416. Lijin Xu, Weiping Chen Organometallics, 2000,19, Examples of Pd(II)-Carbene Complexes

12 Examples of Pd(II)-Carbene Complexes Yuan Han, Han Vinh Huynh, Journal of Organometallic Chemistry, 2007, 692, 3606–3613.

13 hmim = 1-hexyl-3-methylimidazolium Synthesis of Palladium(Il) Carbene Complexes

14 Synthesis of Pd(Il) Carbene Complex Catalyst

15 1 H NMR Spectra of(Hmim)HI (1),PdI 2 (hmim) 2 (2),and Pd(hmim) 2 (OOCCF 3 ) 2 (3) *CDCl 3 2H H CH 3

16 13 C NMR Spectra of (Hmim)HI (1), PdI 2 (hmim) 2 (2), and Pd(hmim) 2 (OOCCF 3 ) 2 (3) *CDCl 3 C C C

19 F NMR of Pd(hmim) 2 (OOCCF 3 ) 2 (3) 17 F

18 IR Spectra of (Hmim)HI (1), PdI 2 (hmim) 2 (2), and Pd(hmim) 2 (OOCCF 3 ) 2 (3) (Hmim)HI (1) PdI 2 (hmim) 2 (2) Pd(hmim) 2 (OOCCF 3 ) 2 (3) 1868 (C=O) imidazole H–C–C & H–C–N bending 2953,2930, imidazole ring ν (C–H) aliphatic ν (C–H) imidazole ν (ring stretching) 3079, , 2928, , , 2933, ,

19 Single-Crystal Structure of PdI 2 (hmim) 2 (2) bond lengths [Å] bond angles [deg] Pd(1)-C(11) Pd(1)-I(1) 2.019(5) (5) N(4)-C(11)-N(3) C(11)-Pd(1)-C(1) I(2)-Pd(1)-I(1) C(11)-Pd(1)-I(2) C(1)-Pd(1)-I(1) 105.0(5) 179.8(2) (2) 89.62(15) 90.27(14) Pd(2)-C(21) Pd(2)-I(3)# (6) (6) N(5)-C(21)-N(6) C(21)-Pd(2)-C(21)#1 I(3)-Pd(2)-I(3)#1 C(21)-Pd(2)-I(3)#1 C(21)#1-Pd(2)-I(3) 105.4(5) 180.0(4) (2) 90.0(2) dihedral angle 8.20 °

20 Bond lengths [Å] Pd(1)-C(1) 2.024(5) Pd(1)-I(1) (5) N(1)-C(1) 1.352(7) N(1)-C(2) 1.387(7) C(2)-C(3) 1.341(8) Bond angles [deg] C(1)-Pd(1)-I(1) 90.27(14) C(11)-Pd(1)-C(1) 179.8(2) I(2)-Pd(1)-I(1) (2) N(2)-C(1)-N(1) 105.2(4) C(1)-N(1)-C(2) 110.6(4) C(3)-C(2)-N(1) 107.0(5) Selective Bond lengths and Bond Angles of PdI 2 (hmim) 2 (2) Lijin Xu, Weiping, Chen, Journal of Organometallic Chemistry, 2000, 598, 409–416.

21 N-Heterocyclic Carbene Complexes of palladium ---- Isolation of cis and trans Isomers Dieter Enders, Heike Gielen. Chem. Ber, 1996, 129, 1483–1488. trans-anti could be dissolved in Et 2 O. trans-syn was not soluble in Et 2 O. cis (yield : 8 %) + trans (yield : 82%) trans-syn : trans-anti = 1: 2.6

22 N-Heterocyclic Carbene Complexes of Palladium ---- cis / trans-isomerization cis (white solid) Yield : 19 % trans (Yellow solid) Yield : 55 % 1 H NMR(trans-syn ) 4.06 (s, 6H, NCH 3 ) 4.44 (t,4H, NCH 2 ) Lijin Xu, Weiping Chen Organometallics, 2000,19, H NMR(trans-anti) 4.09 (s, 6H, NCH 3 ) 4.46 (t,4H, NCH 2 ) trans-anti : trans-syn =1:1 d-CDCl 3 Rt,24 h trans-anti : trans-syn =5:1

PdI 2 (hmim) 2 (2) trans-syn and trans-anti isomerization 23 Rt,12h PdI 2 (hmim) 2 (2) recrystalized from toluene + hexane (1:15) PdI 2 (hmim) 2 (2) d-CDCl NMR 50 °C,12h trans-anti trans-syn + trans-anti

24 NHC-Pd(II) Complex-Catalyzed Strecker Reaction Entry 1~14 TOF(h -1 ) = 1.38 Jamie Jarusiewicz, Yvonne Choe. J. Org. Chem. 2009, 74, 2873–2876. a Reaction condition: 3 mol % Pd catalyst, 0.2 mmol benzaldehyde, 0.2 mmol aniline,0.4 mmol TMSCN, sodium sulfate 0.7 mmol, room temperature stirring in 1 mL of CH 2 Cl 2 b Isolated yield.

25 a Reaction condition: 3 mol % Pd catalyst, 0.2 mmol benzaldehyde, 0.2 mmol aniline,0.4 mmol TMSCN, sodium sulfate 0.7 mmol, room temperature stirring in 1 mL of CH 2 Cl 2 b Isolated yield. Jamie Jarusiewicz, Yvonne Choe. J. Org. Chem. 2009, 74, 2873–2876. TOF (h -1 ) TOF (h -1 ) NHC-Pd(II) Complex-Catalyzed Strecker Reaction

26 Strecker Reaction Catalyzed by K 2 PdCl 4 B. Karmakar, J. Banerji. Tetrahedron Letters. 2010, xx, xxx–xxx. a Reaction condition: 1.0 mmol aldehyde, 1.0 mmol aniline, 1.3 mmol TMSCN, 10 mol % K 2 PdCl 4, room temperature stirring. b Isolated yield. TOF (h -1 ) TOF (h -1 )

Noor-ul H. Khan, Santosh Agrawal. Tetrahedron Letters. 2008,49, 640– Fe(Cp) 2 PF 6 Catalyzed Strecker Reaction a Reaction condition: 5 mol % Fe(Cp) 2 PF 6, 1 mmol aldehyde or ketone, 1 mmol aniline and1.3mmol TMSCN, reaction time 20 min. b isolated yields. TOF (h -1 ) TOF (h -1 )

Fe(Cp) 2 PF 6 Catalyzed Strecker Reaction 28 Noor-ul H. Khan, Santosh Agrawal. Tetrahedron Letters. 2008,49, 640–644.

29 Proposed Mechanism for the Strecker Reaction

30 Pd(Hmim) 2 (OOCCF 3 ) 2 (3) Catalyzed Strecker Reaction Reaction condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline 0.4 mmol TMSCN, sodium sulfate 0.7 mmol, 0.2 mL solvent, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR. SolventTime Conv. (%) TOF (h -1 ) Time Conv. (%) TOF (h -1 ) toluene 5 min min CH 2 Cl THF CH 3 CN neat>99400-

31 Aldehyde Time (min) Conv. (%) TOF (h -1 ) Aldehyde Time (min) Conv. (%) TOF (h -1 ) 3> > > >99400 Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR. Pd(Hmim) 2 (OOCCF 3 ) 2 (3)-Catalyzed Strecker Reaction

32 Aldehyde Time (min) Conv. (%) TOF (h -1 ) Aldehyde Time (min) Conv. (%) TOF (h -1 ) 1> > > > > > Pd(Hmim) 2 (OOCCF 3 ) 2 (3)-Catalyzed Strecker Reaction-(1) Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR.

33 Aldehyde Time (min) Conv. (%) TOF (h -1 ) Aldehyde Time (min) Conv. (%) TOF (h -1 ) 1> > > > Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR. Pd(Hmim) 2 (OOCCF 3 ) 2 (3)-Catalyzed Strecker Reaction-(2)

34 Amine Time (min) Conv. (%) TOF (h -1 ) Amine Time (min) Conv. (%) TOF (h -1 ) 3> > > Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR. Pd(Hmim) 2 (OOCCF 3 ) 2 (3)-Catalyzed Strecker Reaction

35 Pd(Hmim) 2 (OOCCF 3 ) 2 (3)-Catalyzed Strecker Reaction Condition: 0.2 mmol acetophenone, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR Neat +100 mg Sodium Sulfate < 5 % 65 %99 % Neat< 5 % Time (h) TOF(h -1 ) 1.38

36 Pd(Hmim) 2 (OOCCF 3 ) 2 (3) Catalyzed Strecker Reaction under Microwave Irradiation Conditions Condition: 0.2 mmol acetophenone, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim) 2 (OOCCF 3 ) 2. The conversion is determined by 1 H NMR drops-41%-- 4 drops43 %30 %60 %31% 8 drops-40 % drop56 %71 %72 %58 % 2 drops42 %--- 4 drops27 %--- Time (sec) (bmim)HPF w 450 w TOF(h -1 ) 1420

37 Conclusions We have successfully synthesized NHC-carbene Pd(II) complexes (2) and (3), and characterized them by using 1 H-, 13 C, 19 F-NMR, IR spectrocopies. We have successfully demonstrated the highly effective activity of the Pd(II) complex catalyst towards the Strecker reactions. Not many successful synthetic protocols for Strecker reactions of ketones has been reported. We have demonstrated in this study that our target Pd(II) carbene catalyst (3) is highly active for the Strecker reactions of ketones. The Strecker reactions of ketones can be further accelerated under microwave irradiation conditions.