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 / 07 / 29 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 phosphines. 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- and thermal 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

How does the life start on earth 6 Miller experiment – Water, methane, ammonia and hydrogen. Stanley L. Miller. Science 1953, 117,

7 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,

8 Lewis Acid-Catalyzed Strecker Reactions 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 Reactions. 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 Organometallics, 2000, 19, Examples of Pd(II)-Carbene Complexes Yuan Han, Han Vinh Huynh, Journal of Organometallic Chemistry, 2007, 692, 3606–3613.

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 (hmim)HI PdI 2 (hmim) 2

14 Synthesis of Pd(Il) Carbene Complex Catalyst Pd(hmim) 2 (OOCCF 3 ) 2

15 1 H NMR Spectra of (hmim)HI (2), PdI 2 (hmim) 2 (3), and Pd(hmim) 2 (OOCCF 3 ) 2 (4) *CDCl 3 2H H CH 3

16 13 C NMR Spectra of (hmim)HI (2), PdI 2 (hmim) 2 (3), and Pd(hmim) 2 (OOCCF 3 ) 2 (4) *CDCl 3 C C C q, 2 J(C,F) = 36.0 Hz q, 1 J(C,F) = Hz

19 F NMR of Pd(hmim) 2 (OOCCF 3 ) 2 (4) 17 F

18 IR Spectra of (hmim)HI (2), PdI 2 (hmim) 2 (3), and Pd(hmim) 2 (OOCCF 3 ) 2 (4) (hmim)HI (2) PdI 2 (hmim) 2 (3) Pd(hmim) 2 (OOCCF 3 ) 2 (4) 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 (3) 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 ° Range of Pd(II)-C 1.97 ~ 2.30 Å

20 Lijin Xu, Weiping Chen Organometallics, 2000, 19, N-Heterocyclic Carbene Complexes of Palladium ---- cis / trans-Isomerization trans-anti : trans-syn = 1:1 d-CDCl 3 rt, 24 h d-CDCl 3 trans-anti : trans-syn = 5:1

PdI 2 (hmim) 2 (3) trans-syn and trans-anti Isomerization 21 rt, 12h PdI 2 (hmim) 2 (3) recrystalized from toluene + hexane (1:15) PdI 2 (hmim) 2 (3) d-CDCl NMR 50 °C, 12h trans-anti trans-syn : trans-anti = 1:

22 Strecker Reaction Jiacheng Wang, Yoichi Masui, Makoto Onaka Eur. J. Org. Chem. 2010, 1763–1771.

Noor-ul H. Khan, Santosh Agrawal. Tetrahedron Letters. 2008, 49, 640– Examples of Catalytic Strecker Reaction of Ketones Thomas Mathew, Chiradeep Panja, Steevens Alconcel. PNAS. 2007,104, 3703–3706. Jiacheng Wang, Yoichi Masui, Makoto Onaka Eur. J. Org. Chem. 2010, 1763–1771.

24 Jamie Jarusiewicz, Yvonne Choe. J. Org. Chem. 2009, 74, 2873–2876. Examples of Catalytic Strecker Reaction of Ketones Jing Nie, Teng Wanga, Jun An Ma Org. Biomol. Chem. 2010, 8, 1399–1405.

25 AldehydeKetoneAmine Pd(II)-Catalyzed Strecker Reactions

26 Pd(hmim) 2 (OOCCF 3 ) 2 (4) Catalyzed Strecker Reactions Solvent Time (min) Conv. (%) Time (min) Conv. (%) toluene CH 2 Cl THF actonitrile neat5>9925- Reaction Conditions : Catalyst Loading = 3 mol % ; Benzaldehyde = 0.2 mmol; Aniline = 0.2 mmol, TMSCN = 0.4 mmol ; Sodium Sulfate = 0.7 mmol. The conversion is determined by 1 H NMR.

27 Entry Aldehyde (R) Time (min) Conv. (%) Intermediate / Product / Side product 1Ph1>990/100/0 24-ClC 6 H 4 1>990/100/0 34-MeC 6 H 4 1>990/100/0 44-MeOC 6 H 4 1>990/100/0 52-furyl1>990/100/0 62-thienyl1>990/59/41 72-thienyl1>990/90/10 a 83-pyridyl3>990/100/0 9(E)-PhCH=CH1>990/100/0 10butyl1>990/100/0 11cyclohexyl1>990/100/0 12t-butyl1>990/100/0 Reaction Conditions : Aldehyde = 0.2 mmol; Benzylamine = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR. a PdI 2 (hmim) 2 (3) as catalyst (3 mol%). Strecker Reaction Under Catalyst-Free Conditions

28 Entry Aldehyde (R) Time (min) Conv. (%) Int./ Product no cat. condition Conv. (%) Int./ Product 1Ph5>993/97>9969/31 2Ph5937/86 a >9969/31 34-ClC 6 H 4 10>9930/70>9982/18 44-MeC 6 H 4 2>990/ / MeOC 6 H 4 1>990/ /39 62-furyl2>990/ /75 72-thienyl109713/849377/16 83-pyridyl159717/809669/27 9(E)-PhCH=CH4>990/100>9952/48 10cyclohexyl1>990/100>990/100 Reaction Conditions : Catalyst Loading = 3 mol % ; Aldehyde = 0.2 mmol; Aniline = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR. a Pd(hmim) 2 (OOCCF 3 ) 2 (4) as catalyst. PdI 2 (hmim) 2 (3)-Catalyzed Strecker Reactions

29 Reaction Conditions : Catalyst Loading = 3 mol % ; Benzaldehyde = 0.2 mmol; Amine = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR. PdI 2 (hmim) 2 (3)-Catalyzed Strecker Reactions Entry Amine (R) Time (min) Conv. (%) Int./ Product/ Side product no cat. condition Conv. (%) Int./ Product/ Side product 1butyl1950/90/5>990/87/13 2cyclohexyl1>990/94/6>990/88/12 3Ph5>993/97/0>9969/31/0 44-ClC 6 H 4 5>990/100/0>9978/22/0 54-MeC 6 H 4 5>990/100/09863/35/0 6piperidine20920/77/15910/62/29 7pyrrolidine15970/89/8900/86/4 8morpholine20>990/92/8>990/82/18

30 Entry Aldehyde (R) Time (min) Yield (%) Reported Data Time (min) Yield (%) Reference 1Ph Masui Y, Chem.Eur. J., ClC 6 H Najera C., Synthesis, MeC 6 H Masui Y, Chem.Eur. J., MeOC 6 H Masui Y, Chem.Eur. J., furyl Masui Y, Chem.Eur. J., thienyl Abaee M. S., Tetrahedron Lett., pyridyl Panja C., Synlett., (E)-PhCH=CH Panja C., Synlett., cyclohexyl Acosta F. C., Commun., 2009 Reaction Conditions : Catalyst Loading = 3 mol % ; Aldehyde = 0.2 mmol; Aniline = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR. Comparison of 3-Catalyzed Strecker Reactions with Reported Data

31 Entry Amine (R) Time (min) Yield (%) Reported Data Time (min) Yield (%) Reference 1butyl Masui Y, Chem.Eur. J., cyclohexyl Najera C., Synthesis, Ph Masui Y, Chem.Eur. J., ClC 6 H Masui Y, Chem.Eur. J., MeC 6 H Abaee M. S., Tetrahedron Letters, piperidine Azizi N., Synthetic Communications, pyrrolidine Azizi N., Synthetic Communications, morpholine Desai U. V., Monatshefte fur Chemie., 2007 Reaction Conditions : Catalyst Loading = 3 mol % ; Benzaldehyde = 0.2 mmol; Amine = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR. Comparison of 3-Catalyzed Strecker Reactions with Reported Data

32 NeatNeat mg Na 2 SO 4 Time (h) Conv. (%) Time (h) Conv. (%) cat. 3cat. 4cat. 3cat <51244< ­ 18-- ­- 2454<52448<5 Reaction Conditions : Catalyst Loading = 3 mol % ; Acetophenone = 0.2 mmol; Aniline = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR. PdI 2 (hmim) 2 (3) and Pd(hmim) 2 (OOCCF 3 ) 2 (4)-Catalyzed Strecker Reactions of Ketone

33 EntryMW cat. 3cat. 4 Time (s) Conv. (%) Time (s) Conv. (%) Microwave-Assisted PdI 2 (hmim) 2 (3) and Pd(hmim) 2 (OOCCF 3 ) 2 (4)-Catalyzed Strecker Reaction of Ketones Reaction Conditions : Catalyst Loading = 3 mol % ; Acetophenone = 0.2 mmol; Aniline = 0.2 mmol, TMSCN = 0.4 mmol. The conversion is determined by 1 H NMR.

34 Microwave-Assisted PdI 2 (hmim) 2 (3) and Pd(hmim) 2 (OOCCF 3 ) 2 (4)-Catalyzed Strecker Reactions EntryR1R1 R2R2 cat.3cat.4 Time (s) Conv. (%) Time (s) Conv. (%) 1Ph MeOC 6 H Ph4-MeOC 6 H MeC 6 H ClC 6 H MeOC 6 H 4 Ph BrC 6 H 4 Ph MeOC 6 H Ph naphthyl4-MeOC 6 H MeOC 6 H furylPh pyridyl Ph MeOC 6 H ′-methoxy propiophenone Ph Reaction Conditions : Catalyst Loading = 3 mol % ; Ketone = 0.2 mmol; Amine = 0.2 mmol, TMSCN = 0.4 mmol; (Bmim)PF 6 = 2 drops; Power = 150W. The conversion is determined by 1 H NMR.

35 PdI 2 (hmim) 2 (3)-Catalyzed Strecker Reactions Benzyl amine (pK b = 4.67) Aniline (pK b = 9.3) Kobayashi S.; Tsuchiya Y.; Mukaiyama T. Chemistry Letters, 1991,

36 EntryR1R1 R2R2 cat. 3 Reported Data Time (s) Conv. (%) Time (h) Conv. (%) 1Ph b 23-MeOC 6 H c 3Ph4-MeOC 6 H c 44-MeC 6 H a 54-ClC 6 H e 64-MeOC 6 H 4 Ph e 7 4-BrC 6 H 4 Ph a 84-MeOC 6 H c 9Ph b 102-naphthyl4-MeOC 6 H c 113-MeOC 6 H c 122-furylPh d 13 3-pyridyl Ph d 144-MeOC 6 H c 15 4′-methoxy propiophenone Ph e Reaction Conditions : Catalyst Loading = 3 mol % ; Ketone = 0.2 mmol; Amine = 0.2 mmol, TMSCN = 0.4 mmol; (Bmim)PF 6 = 2 drops; Power = 150W. The conversion is determined by 1 H NMR. a Ga(OTf) 3, b Fe(Cp) 2 PF 6, c BINOL-derived phosphoric acid, d Pd II -NHC, e Sn-Mont Comparison of 3-Catalyzed Strecker Reactions with Reported Data

37 EntryR1R1 R2R2 cat. 4Reported Data Time (s) Conv. (%) Time (h) Conv. (%) 1Ph b 23-MeOC 6 H c 3Ph4-MeOC 6 H c 44-MeC 6 H a 54-ClC 6 H e 64-MeOC 6 H 4 Ph e 7 4-BrC 6 H 4 Ph a 84-MeOC 6 H c 9Ph b 102-naphthyl4-MeOC 6 H c 113-MeOC 6 H c 122-furylPh d 13 3-pyridyl Ph d 144-MeOC 6 H c 15 4′-methoxy propiophenone Ph e Reaction Conditions : Catalyst Loading = 3 mol % ; Ketone = 0.2 mmol; Amine = 0.2 mmol, TMSCN = 0.4 mmol; (Bmim)PF 6 = 2 drops; Power = 150W. The conversion is determined by 1 H NMR. a Ga(OTf) 3, b Fe(Cp) 2 PF 6, c BINOL-derived phosphoric acid, d Pd II -NHC, e Sn-Mont Comparison of 4-Catalyzed Strecker Reactions with Reported Data

38 Proposed Mechanism for Strecker Reaction

39 Conclusions We have successfully synthesized NHC-carbene Pd(II) complexes (3) and (4), and characterized them by using 1 H-, 13 C, 19 F-NMR, IR spectrocopies, as well as X-ray crystallography. We have successfully demonstrated the highly effective activity of the Pd(II) NHC-carbene 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) NHC-carbene catalyst (3) and (4) is highly active for the Strecker reactions of ketones under microwave irradiation conditions.