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 / 17Department 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.

P P PPO

OO

P(Bu)3 P(OiPr)3 P(Me)3 P(o-tolyl)3

25 mL 211.5 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, 1290-1309.

Herrmann, W. A.; Öfele, K; Elison, M.; Kühn, F. E.; Roesky, P. W. J. Organomet. Chem. 1994, 480, C7-C9.

N NMe Me

W

COCOOCCOOC V

NHCCHN

NHCCHNCl

ClTi ClCl

ClCl

NN

N N

Me Me

MeMe

Re OO

OMe

N NMe Me Ru

PCy3

Ph

NNMesMes

ClCl

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 1850.

Two novel organogallium(III) complexes were tested in vitro against human tumour.

R1

O

HH2N

R2 NaCN

AcOH

HNR2

R1 CN

H+ HNR2

R1 CO2H

Santiago Gomez-Ruiz , Milena R. Journal of Organometallic Chemistry 2009,694, 2191–2197.

Strecker, D. Ann.Chem. Pharm. 1850,75, 27-45.

The Various Modes of α-Aminonitrile Reactivity

7Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359-373.

8

Lewis Acid-Catalyzed Strecker Reaction Lewis acid catalysts Et3N 、 InCl3 、 Ga(OTf)3 、 BiCl3

Paraskar, A. S.; Sudalai, A. Tetrahedron Lett. 2006, 47, 5759-5762. Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529-2532. Surya Prakash, G. K.; Mathew, T. ; Panja, C.; Alconcel, S.; Vaghoo, H.; Do, C.; Olah, G. A. PNAS 2007, 104, 3703-3706. De, S. K. ; Gibbs, R. A. Tetrahedron Lett. 2004, 45, 7407-7408.

Transition metal Lewis acid catalysts RuCl3 、 NiCl2 、 Sc(OTf)3 、 Cu(OTf)2

De, S. K. Synth. Commun. 2005, 35, 653-656. De, S. K. J. Mol. Catal. A: Chem. 2005, 225, 169-171.

Lanthanide Lewis acid catalysts Pr(OTf)3 、 La(O-i-Pr) 、 Yb(OTf)3

De, S. K. Synth. Commun. 2005, 35, 961-966.

Others KSF 、 I2

Yadav, J. S.; Subba Reddy, B. V.; Eeshwaraiah B.; Srinivas, M. Tetrahedron 2004, 60, 1767-1771. Royer, L.; De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 4595-4597.

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 theStrecker Reaction.

Greener catalysis –solventless and microwave conditions.

10Toshikazu Hirao, Kenji Tsubata . Tetrahedron Letters 1978 , 18, 1535 - 1538.

Pd(II)Cl2(RNC)2 NH2CHCH(OC2H5)2R1 R2

PdCl

Cl

CNHR

NHCHCH(OC2H5)2

R1 R2

NHR

H -2C2H5OH

PdCl

Cl

CN

N

NHRR2

R1

R

H

24 h

rt

The First Palladium(II) Carbene Complexes

11Lijin Xu, Weiping, Chen, Journal of Organometallic Chemistry, 2000, 598, 409–416.

Lijin Xu, Weiping Chen Organometallics, 2000,19, 1123-1127 .

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

BrNaI

acetone reflux, 24 hI

NN

NN

I70oC, 8 h

(hmim)HI(1)

yield = 90 % yield = 95 %

N N

Pd II

NN

trans-syn

N N

Pd II

NN

trans-syn

PdI2(hmim)2(2)

NN

I

(hmim)HI(1)

Pd(OAC)2

THF reflux, 3h

yield = 70%

14

Synthesis of Pd(Il) Carbene Complex Catalyst

N N

Pd II

NN

trans-syn

CH3CN, 3h

yield = 90%

NN

Pd

NN

O CF3

O

O CF3

O

Pd(hmim)2(OOCCF3)2(3)

AgO CF3

O

N N

Pd II

NN

trans-syn

PdI2(hmim)2(2)

15

1H NMR Spectra of(Hmim)HI (1),PdI2(hmim)2 (2),and Pd(hmim)2(OOCCF3)2 (3)

*CDCl3

2HH

NN

Pd

NN

O CF3

O

O CF3

O

Pd(hmim)2(OOCCF3)2(3)

CH3

NN

I

(hmim)HI(1)

H

H H

N NH3C

Pd II

NNH3C

N NH3C

Pd II

NNCH3

trans-syn trans-syn

PdI2(hmim)2(2)

16

13C NMR Spectra of (Hmim)HI (1), PdI2(hmim)2 (2), and Pd(hmim)2(OOCCF3)2 (3)

*CDCl3

NC

N

I(hmim)HI

(1)

C

C

C

N N

Pd II

NN

N N

Pd II

NNC

trans-syn trans-syn

PdI2(hmim)2(2)

C

C

C

NN

C

Pd

NN C

O CF3

O

O CF3

O

Pd(hmim)2(OOCCF3)2(3)

19F NMR of Pd(hmim)2(OOCCF3)2 (3)

17

NN

Pd

NN

O CF3

O

O CF3

O

Pd(hmim)2(OOCCF3)2(3)

F

4000 3500 3000 2500 2000 1500 1000 50040

45

50

55

60

65

70

75

80

85

90

95

100

tran

smitt

ance

(a.

u.)

wavenumber(cm-1)18

IR Spectra of (Hmim)HI (1), PdI2(hmim)2 (2), and Pd(hmim)2(OOCCF3)2 (3)

(Hmim)HI (1)

PdI2(hmim)2 (2)

Pd(hmim)2(OOCCF3)2 (3)

1868(C=O)

1166

1219

imidazole H–C–C & H–C–N bending

2953,2930,2857 1569

imidazole ring ν (C–H) aliphatic ν (C–H)

imidazole ν (ring stretching)

3079,3140

2954, 2928, 28573113, 3149

2957, 2933, 28613133, 3162

1566

1576

1190

19

Single-Crystal Structure of PdI2(hmim)2 (2)

bond lengths [Å] bond angles [deg]

Pd(1)-C(11)Pd(1)-I(1)

2.019(5)2.6066(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)179.22(2)89.62(15)90.27(14)

Pd(2)-C(21) Pd(2)-I(3)#1

2.032(6)2.6059(6)

N(5)-C(21)-N(6)C(21)-Pd(2)-C(21)#1I(3)-Pd(2)-I(3)#1C(21)-Pd(2)-I(3)#1C(21)#1-Pd(2)-I(3)

105.4(5)180.0(4)180.00(2)90.0(2)90.0(2)

dihedral angle8.20 °

20

Bond lengths [Å]Pd(1)-C(1) 2.024(5)Pd(1)-I(1) 2.6066(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) 179.22(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 PdI2(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 Et2O. trans-syn was not soluble in Et2O.

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 %

1H NMR(trans-syn )4.06 (s, 6H, NCH3)4.44 (t ,4H, NCH2 )Lijin Xu, Weiping Chen Organometallics, 2000,19, 1123-1127 .

1H NMR(trans-anti) 4.09 (s, 6H, NCH3)4.46 (t ,4H, NCH2 )

trans-anti : trans-syn =1:1

d-CDCl3

Rt ,24 htrans-anti : trans-syn =5:1

PdI2(hmim)2 (2) trans-syn and trans-anti isomerization

23

Rt ,12h

PdI2(hmim)2 (2) recrystalized from toluene + hexane (1:15)

PdI2(hmim)2(2)

d-CDCl3

200 NMR

50 °C,12h

trans-anti trans-syn + trans-anti

4.3634.3254.287

+3.952

4.3804.3624.3304.3014.285

+3.9513.935

N N

Pd II

NN

trans-syn

24

NHC-Pd(II) Complex-Catalyzed Strecker Reaction

Entry 1~14TOF(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 CH2Cl2 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 CH2Cl2 b Isolated yield.

Jamie Jarusiewicz, Yvonne Choe. J. Org. Chem. 2009, 74, 2873–2876.

TOF (h-1) 1.18

0.68

0.80

0.86

0.94

TOF (h-1) 1.38

1.19

1.31

0.23

0.61

NHC-Pd(II) Complex-Catalyzed Strecker Reaction

26

Strecker Reaction Catalyzed by K2PdCl4

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 % K2PdCl4, room temperature stirring.b Isolated yield.

TOF (h-1) 50

20

20

20

10

14.2

10

10

TOF (h-1) 20

20

20

10

10

8.3

10

10

13.3

Noor-ul H. Khan, Santosh Agrawal . Tetrahedron Letters. 2008,49, 640–644.

27

Fe(Cp)2PF6 Catalyzed Strecker Reaction

a Reaction condition: 5 mol % Fe(Cp)2PF6 , 1 mmol aldehyde or ketone , 1 mmol aniline and1.3mmol TMSCN, reaction time 20 min.b isolated yields.

TOF (h-1) 56.4

55.2

49.2

51.6

48.6

54

53.4

TOF (h-1) 56.4

51

51.6

49.2

40.8

50.4

52.2

Fe(Cp)2PF6 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(OOCCF3)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(OOCCF3)2 . The conversion is determined by 1H NMR.

 Solvent TimeConv.(%)

TOF(h-1)

TimeConv.(%)

TOF(h-1)

toluene

5 min

52 208

25 min

62 49.6

CH2Cl2 55 220 87 69.6

THF 5 20 53 42.4

CH3CN 59 236 89 71.2

neat >99 400 -

31

 AldehydeTime(min)

Conv.(%)

TOF(h-1)

 AldehydeTime(min)

Conv.(%)

TOF(h-1)

3 >99 666 15 97 130

20 80 80 15 90 120

2 >99 1000 5 >99 400

5 >99 400

H

O

H

O

Cl

CHO

CHO

MeO

N

H

O

H

O

H

O

R H

OTMSCN

3 mol % cat.(3)

Neat, RT

NH2

R NH

CN

Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)2 . The conversion is determined by 1H NMR.

Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker Reaction

32

 AldehydeTime(min)

Conv.(%)

TOF(h-1)

 AldehydeTime(min)

Conv.(%)

TOF(h-1)

1 >99 2000 1 >99 2000

1>99

2000 1>99

2000

1>99

2000 1>99

2000

Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker Reaction-(1)

H

O

H

O

Cl

CHO

CHO

MeO

R H

OTMSCN

3 mol % cat.(3)

Neat, RT

NC

R

HNNH2

O H

O

S H

O

Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)2 . The conversion is determined by 1H NMR.

33

 AldehydeTime(min)

Conv.(%)

TOF(h-1)

 AldehydeTime(min)

Conv.(%)

TOF(h-1)

1 >99 2000

1>99

2000 1>99

2000

1>99

2000

H

O

R H

OTMSCN

3 mol % cat.(3)

Neat, RT

NC

R

HNNH2

N

H

O

H

O

H

O

H

O

Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)2 . The conversion is determined by 1H NMR.

Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker Reaction-(2)

34

 AmineTime(min)

Conv.(%)

TOF(h-1)

 AmineTime(min)

Conv.(%)

TOF(h-1)

3 >99 666 5 95 380

5 >99 400 5 99 400

5 >99 400

5 90 360

H

O

TMSCN3 mol % cat.(3)

Neat, RT NHR

RNH2NC

NH2

NH2

NH2

NH

NH

O NH

Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)2 . The conversion is determined by 1H NMR.

Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker Reaction

35

Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker Reaction

NH

H3C CNO

TMSCN3 mol % cat.(3)

Neat, RT

RNH2

Condition: 0.2 mmol acetophenone, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)2 . The conversion is determined by 1H NMR.

1 2 14 24

Neat +100 mgSodium Sulfate

< 5 % < 5 % 65 % 99 %

Neat < 5 % < 5 % < 5 % < 5 %

Time (h)

TOF(h-1)1.38

36

Pd(Hmim)2(OOCCF3)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(OOCCF3)2 . The conversion is determined by 1H NMR.

30 40 60  80

2 drops - 41% - -

4 drops 43 % 30 % 60 % 31%

8 drops - 40 % - -

40 60  70 80

1 drop 56 % 71 % 72 % 58 %

2 drops 42 % - - -

4 drops 27 % - - -

Time (sec)

Time (sec)

(bmim)HPF6

(bmim)HPF6

600 w

450 w

TOF(h-1)1420

NH

H3C CNO

TMSCN3 mol % cat.(3)

Microwave

RNH2

37

ConclusionsWe have successfully synthesized NHC-carbene Pd(II) complexes (2) and (3) , and characterized them by using 1H- ,13C , 19F-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 theStrecker reactions of ketones.

The Strecker reactions of ketones can be further accelerated under microwave irradiation conditions.