Synthesis and Characterization of N-Heterocyclic
Carbene Palladium(II) Complexes. The Catalytic
Application on Strecker Synthesis of αaminonitriles
學生：洪柏楷
指導教授：于淑君 博士
2010 / 05 / 17
Department of Chemistry & Biochemistry
Chung Cheng University
1
Phosphine Ligand
 Phosphines are electronically and sterically tunable.
 Expensive.
P
P(Bu)3
25 mL
211.5 USD
O
P O
O
P(OiPr)3
100 mL
31.9 USD
P
P
P(Me)3
P(o-tolyl)3
25 G
396 USD
10G
135.5USD
 Air/water sensitive and thermally unstable.
 Metal leaching.
 Chemical waste - water bloom.
2
N-Heterocyclic Carbenes
[M]
 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.
3
N-Heterocyclic Carbenes as Ligands
- In the early 90's NHC were found to have bonding properties similar to
trialklyphosphanes and alkylphosphinates.
Herrmann, W. A.; Öfele, K; Elison, M.; Kühn, F. E.; Roesky, P. W. J. Organomet. Chem. 1994, 480, C7-C9.
- compatible with both high and low oxidation state metals
- examples:
N Me
Me N
OC
CO
OC W CO
CO
Cl
CHN
NHC
V
CHN
NHC
Cl
Me
N
N
Me
Cl
Cl
Cl Ti Cl
Me
N Me
N
Me
O
N
N
Re O Mes
Mes
O
Cl Ru
Ph
Me N
N Me
Cl
PCy3
- reaction employing NHC's as ligands:
Herrmann, W. Angew. Chem. Int. Ed. 2002, 41, 1290-1309.
4
The Catalytic Applications of Pd(II)
 Heck reaction
 C-H Activation of Methane
 Suzuki–Miyaura Reaction
 Oxidation of Alcohols
 Carbon-Surfur Coupling Reactions
 Reductive Aldol Reaction
 Buchwald-Hartwig Reactions
 Allylation of Aldehydes
 Etherification Reaction
 Strecker Reaction
 Ethylene-CO copolymerization Reaction
5
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).
O
R1
H
H2N
R2
NaCN
AcOH
HN
R1
R2
+
H
CN
HN
R1
R2
CO2H
 Adolph Strecker was the first to understand this organic reaction at 1850.
Strecker, D. Ann.Chem. Pharm. 1850,75, 27-45.
 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.
6
The Various Modes of α-Aminonitrile Reactivity
Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359-373.
7
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.
8
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.
9
The First Palladium(II) Carbene Complexes
Pd(II)Cl2(RNC)2
NH2CHCH(OC2H5)2
R1 R2
24 h
rt
Cl
NHR
NHR
Pd
C
Cl
NHCHCH(OC2H5)2
R1 R2
H
-2C2H5OH
NHR R
N
Pd
C
Cl
N
H
Cl
R2
R1
Toshikazu Hirao, Kenji Tsubata . Tetrahedron Letters 1978 , 18, 1535 - 1538. 10
Examples of Pd(II)-Carbene Complexes
Lijin Xu, Weiping Chen Organometallics, 2000,19, 1123-1127 .
Lijin Xu, Weiping, Chen, Journal of Organometallic Chemistry, 2000, 598, 409–416.
11
Examples of Pd(II)-Carbene Complexes
Yuan Han, Han Vinh Huynh, Journal of Organometallic Chemistry, 2007, 692, 3606–3613. 12
Synthesis of Palladium(Il) Carbene Complexes
N
N
NaI
Br
I
acetone reflux, 24 h
yield = 90 %
N
N
o
70 C, 8 h
I
yield = 95 %
(hmim)HI
(1)
hmim = 1-hexyl-3-methylimidazolium
N
N
N
N
N
Pd(OAC)2
N
I Pd
I
I
I Pd I
THF reflux, 3h
yield = 70%
N
N
N
N
(hmim)HI
(1)
trans-syn
trans-syn
PdI2(hmim)2
(2)
13
Synthesis of Pd(Il) Carbene Complex Catalyst
N
N
I Pd
N
N
O
N
AgO
N
CF3
I Pd I
I
N
N
N
Pd
CH3CN, 3h
yield = 90%
trans-syn
O
N
N
N
O
O
CF3
CF3
O
trans-syn
PdI2(hmim)2
(2)
Pd(hmim)2(OOCCF3)2
(3)
14
1H
NMR Spectra of(Hmim)HI (1),PdI2(hmim)2 (2),and
Pd(hmim)2(OOCCF3)2 (3)
*CDCl3
N
O
N
Pd
N
N
O
O
CF3
CF3
O
Pd(hmim)2(OOCCF3)2
(3)
CH3
H3C
I Pd
H3C
N
N
N
N
I Pd
I
H3C
N
N
CH3
N
I
N
trans-syn
trans-syn
PdI2(hmim)2
(2)
H
N
N
H
H
I
H
2H
(hmim)HI
(1)
15
13C
NMR Spectra of (Hmim)HI (1), PdI2(hmim)2 (2),
and Pd(hmim)2(OOCCF3)2 (3)
*CDCl3
N
N
O
C
Pd
N C
O
O
CF3
CF3
C
O
N
Pd(hmim)2(OOCCF3)2
(3)
N
N
N
N
C
C
I Pd I
C
N
N
I Pd I
C
N
N
Ctrans-syn
trans-syn
PdI2(hmim)2
(2)
N
C
N
(hmim)HI
(1)
I
C
16
19F
NMR of Pd(hmim)2(OOCCF3)2 (3)
N
O
N
Pd
N
N
O
O
CF3
CF3
O
F
Pd(hmim)2(OOCCF3)2
(3)
17
IR Spectra of (Hmim)HI (1), PdI2(hmim)2 (2), and
Pd(hmim)2(OOCCF3)2 (3)
100
95
90
3133, 3162
2957, 2933, 2861
1868
(C=O)
85
transmittance (a.u.)
Pd(hmim)2(OOCCF3)2 (3)
1576
1190
80
75
PdI2(hmim)2 (2)
70
3113, 3149
1566
1219
2954, 2928, 2857
65
60
55
imidazole ν (ring stretching)
(Hmim)HI (1)
50
45
40
4000
1166
3079,3140
imidazole ring ν (C–H)
3500
3000
2953,2930,2857
aliphatic ν (C–H)
2500
1569
2000
1500
-1
wavenumber(cm )
imidazole H–C–C
& H–C–N bending
1000
500
18
Single-Crystal Structure of PdI2(hmim)2 (2)
bond lengths [Å]
Pd(1)-C(11)
Pd(1)-I(1)
Pd(2)-C(21)
Pd(2)-I(3)#1
bond angles [deg]
2.019(5)
2.6066(5)
2.032(6)
2.6059(6)
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)
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)
180.00(2)
90.0(2)
90.0(2)
dihedral angle
8.20 °
19
Selective Bond lengths and Bond Angles of
PdI2(hmim)2 (2)
Bond lengths
Pd(1)-C(1)
Pd(1)-I(1)
N(1)-C(1)
N(1)-C(2)
C(2)-C(3)
Bond angles
C(1)-Pd(1)-I(1)
C(11)-Pd(1)-C(1)
I(2)-Pd(1)-I(1)
N(2)-C(1)-N(1)
C(1)-N(1)-C(2)
C(3)-C(2)-N(1)
[Å]
2.024(5)
2.6066(5)
1.352(7)
1.387(7)
1.341(8)
[deg]
90.27(14)
179.8(2)
179.22(2)
105.2(4)
110.6(4)
107.0(5)
20
Lijin Xu, Weiping, Chen, Journal of Organometallic Chemistry, 2000, 598, 409–416.
N-Heterocyclic Carbene Complexes of palladium
---- Isolation of cis and trans Isomers
cis (yield : 8 %) + trans (yield : 82%)
trans-syn : trans-anti = 1: 2.6
trans-anti could be dissolved in Et2O.
trans-syn was not soluble in Et2O.
Dieter Enders, Heike Gielen. Chem. Ber, 1996, 129, 1483–1488. 21
N-Heterocyclic Carbene Complexes of Palladium
---- cis / trans-isomerization
cis
(white solid)
Yield : 19 %
Rt ,24 h
trans
(Yellow solid)
Yield : 55 %
trans-anti : trans-syn
=5:1
d-CDCl3
trans-anti : trans-syn
=1:1
Lijin Xu, Weiping Chen Organometallics, 2000,19, 1123-1127 .
1H
NMR(trans-anti)
4.09 (s, 6H, NCH3)
4.46 (t ,4H, NCH2 )
1H
NMR(trans-syn )
4.06 (s, 6H, NCH3)
4.44 (t ,4H, NCH2 )
22
PdI2(hmim)2 (2) trans-syn and trans-anti
isomerization
PdI2(hmim)2 (2) recrystalized
from toluene + hexane (1:15)
I Pd
N
4.380
4.362
4.330
4.301
4.285
+
3.951
3.935
trans-anti
N
N
4.363
4.325
4.287
+
3.952
I
Rt ,12h
N
trans-syn
+
trans-anti
trans-syn
200 NMR
50 °C,12h
d-CDCl3
PdI2(hmim)2(2)
23
NHC-Pd(II) Complex-Catalyzed Strecker Reaction
Entry 1~14
TOF(h-1) = 1.38
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
24
b Isolated yield.
Jamie Jarusiewicz, Yvonne Choe. J. Org. Chem. 2009, 74, 2873–2876.
NHC-Pd(II) Complex-Catalyzed Strecker Reaction
TOF
(h-1)
1.38
TOF
(h-1)
1.18
1.19
0.68
1.31
0.80
0.86
0.23
0.61
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. 25
0.94
Strecker Reaction Catalyzed by K2PdCl4
TOF (h-1)
50
TOF (h-1)
20
20
20
20
20
10
20
10
10
8.3
14.2
10
10
10
10
a
Reaction condition: 1.0 mmol aldehyde, 1.0 mmol aniline,
1.3 mmol TMSCN, 10 mol % K2PdCl4, room temperature stirring.
b Isolated yield.
13.3
26
B. Karmakar, J. Banerji. Tetrahedron Letters. 2010, xx, xxx–xxx.
Fe(Cp)2PF6 Catalyzed Strecker Reaction
TOF (h-1)
56.4
TOF (h-1)
56.4
51
55.2
49.2
51.6
49.2
51.6
48.6
40.8
54
50.4
53.4
52.2
a
Reaction condition: 5 mol % Fe(Cp)2PF6 , 1 mmol aldehyde or ketone ,
1 mmol aniline and1.3mmol TMSCN, reaction time 20 min.
27
b isolated yields.
Noor-ul H. Khan, Santosh Agrawal . Tetrahedron Letters. 2008,49, 640–644.
Fe(Cp)2PF6 Catalyzed Strecker Reaction
28
Noor-ul H. Khan, Santosh Agrawal . Tetrahedron Letters. 2008,49, 640–644.
Proposed Mechanism for the Strecker Reaction
29
Pd(Hmim)2(OOCCF3)2 (3) Catalyzed
Strecker Reaction
Conv.
(%)
TOF
(h-1)
Conv.
(%)
TOF
(h-1)
toluene
52
208
62
49.6
CH2Cl2
55
220
87
69.6
5
20
53
42.4
CH3CN
59
236
89
71.2
neat
>99
400
-
Solvent
THF
Time
5 min
Time
25 min
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.
30
Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed
Strecker Reaction
O
R
NH2
TMSCN
H
R
Neat, RT
Aldehyde
CN
3 mol % cat.(3)
Time
(min)
Conv.
(%)
TOF
(h-1)
Aldehyde
N
H
Time
(min)
Conv.
(%)
TOF
(h-1)
15
97
130
15
90
120
5
>99
400
O
O
H
3
>99
666
H
N
O
O
H
20
80
H
80
Cl
CHO
CHO
O
2
>99
1000
5
>99
400
H
MeO
Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)231
.
1
The conversion is determined by H NMR.
Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker
Reaction-(1)
O
R
NH2
H
Aldehyde
3 mol % cat.(3)
TMSCN
NC
Neat, RT
Time
(min)
Conv.
(%)
TOF
(h-1)
Aldehyde
H
N
R
Time
(min)
Conv.
(%)
TOF
(h-1)
1
>99
2000
O
H
1
>99
CHO
2000
MeO
O
H
1
>99
O
2000
O
H
1
>99
2000
Cl
CHO
1
>99
O
2000
S
H
1
>99
2000
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.
32
Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker
Reaction-(2)
O
R
NH2
H
Aldehyde
3 mol % cat.(3)
TMSCN
NC
Neat, RT
Time
(min)
Conv.
(%)
TOF
(h-1)
O
Aldehyde
Time
(min)
H
N
R
Conv.
(%)
TOF
(h-1)
O
1
H
>99
2000
H
N
O
H
1
O
H
1
>99
>99
O
2000
H
1
>99
2000
2000
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
Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker
O
Reaction
H
3 mol % cat.(3)
TMSCN
RNH2
NC
Neat, RT
Amine
NH2
NH2
NH2
N
H
Time
(min)
Conv.
(%)
TOF
(h-1)
3
>99
666
5
>99
400
5
>99
400
5
90
360
Amine
N
H
O
NH
NHR
Time
(min)
Conv.
(%)
TOF
(h-1)
5
95
380
5
99
400
Condition: 0.2 mmol benzaldehyde, 0.2 mmol aniline, 0.4 mmol TMSCN, RT, 3 mol % Pd (Hmim)2(OOCCF3)2 .
34
The conversion is determined by 1H NMR.
Pd(Hmim)2(OOCCF3)2 (3)-Catalyzed Strecker
Reaction
O
RNH2
TMSCN
3 mol % cat.(3)
H3C
N
H
Neat, RT
Time (h)
1
2
14
CN
24
Neat +100 mg
Sodium Sulfate
<5%
<5%
65 %
99 %
Neat
<5%
<5%
<5%
<5%
TOF(h-1)
1.38
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.
35
Pd(Hmim)2(OOCCF3)2 (3) Catalyzed Strecker
Reaction under Microwave Irradiation Conditions
O
RNH2
TMSCN
3 mol % cat.(3)
H3C
N
H
Microwave
Time (sec)
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 %
-
-
-
(bmim)HPF6
600 w
Time (sec)
(bmim)HPF6
450 w
CN
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.
TOF(h-1)
1420
36
Conclusions
 We 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 the
Strecker reactions of ketones.
 The Strecker reactions of ketones can be further accelerated
under microwave irradiation conditions.
37