Easily accessible ferrocenyl N-P/S type ligands and their applications in asymmetric allylic substitutions

Article abstract of DOI:10.1016/j.tetasy.2005.12.037

Easily accessible novel 1,2-disubstituted phosphinamidite-thioether ligands based on a ferrocene motif have been developed, and successfully applied for asymmetric allylic substitutions with excellent yields and enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2005.12.037

Tetrahedron: Asymmetry 17 (2006) 497–499
Easily accessible ferrocenyl N-P/S type ligands
and their applications in asymmetric allylic substitutions
a
a
a
a
Fuk Loi Lam, Terry T. L. Au-Yeung, Hong Yee Cheung, Stanton H. L. Kok,
a
a
a,b,
*
Wing Sze Lam, Kwok Yin Wong and Albert S. C. Chan
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis,
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong
b
State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Shenzhen, China
Received 6 December 2005; accepted 14 December 2005
Available online 10 March 2006
Abstract—Easily accessible novel 1,2-disubstituted phosphinamidite-thioether ligands based on a ferrocene motif have been devel-
oped, and successfully applied for asymmetric allylic substitutions with excellent yields and enantioselectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
CH3
SBut
PR2
O
Me
Me
Ph P
2
OPAr2
The transition metal-catalyzed asymmetric allylic substi-
tution has become a powerful tool for enantioselective
carbon–carbon and carbon–heteroatom bond forma-
tion. Several classes of chiral ligands, such as bisphos-
phines, monodentate phosphines, and P/N mixed-
PPh2
Fe
Fe
RS
Me
1
Evans
Carretero
5
1
2
3
–5
donor ligands have been extensively studied and pro-
ven to be effective ligands for Pd-catalyzed asymmetric
allylic substitution reactions. In the literature, few re-
ports concern the use of chiral P/S mixed donors for
metal-catalyzed asymmetric reactions6 (Fig. 1). Seminal
work by Evans et al. showed that O-P/S mixed-donor
ligands could mediate Rh-catalyzed hydrogenation
reactions and Pd-catalyzed allylic alkylation with
CH3
CH3
N
O
PPh2
O
O
O
O
PPh2
P
P
Fe
Fe
–9
6
7
Figure 1.
7
enantioselectivity up to 98% ee. Recent works by Car-
retero et al. also revealed that several P/S ligands were
8
effective for Pd-catalyzed allylic substitution reactions,
fully applied for Rh-catalyzed hydrogenation of dehy-
9
,12
ring opening of oxa- and aza-bicyclic alkenes,
aza
dro-a-amino acid derivatives to give hydrogenated
1
0
14
Diels–Alder reactions, and 1,3-dipolar cycloaddition
product with excellent enantiopurity. Further to these
1
1
of azomethine ylides.
efforts, we herein report that bidendate ferrocenyl phos-
phinamidite-thioether ligands, such as 2, are promising
ligands for asymmetric catalysis. The results of their
application in asymmetric allylic alkylation and amina-
tion will be described.
Ferrocene-based chiral phosphines have found impor-
tant applications for metal-catalyzed asymmetric reac-
tions. Recently, we developed chelating ferrocenyl
1
3
phosphine-phosphinites 5, phosphine-phosphoramidites
6
, and phosphine-phosphites 7. These have been success-
2. Results and discussion
*
Corresponding author. Tel.: +852 27665607; fax: +852 23649932;
e-mail: bcachan@polyu.edu.hk
Scheme 1 depicts the synthetic route for ferrocenyl
phosphinamidite-thioether ligands 2. Starting from the
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.037

498
F. L. Lam et al. / Tetrahedron: Asymmetry 17 (2006) 497–499
CH
3
SR
Fe
CH
3
did not result in better enantioselectivity (ca. 86% ee;
entries 2 and 3). Herein, Zn(OAc) was found to be the
sec-BuLi
RSSR
2
NMe2
NMe
2
best additive; up to 90.2% ee was attained for the allylic
substitution reaction (entry 4).
Fe
6
SR
Fe
0-90%
1
3
The effect of solvent for the Pd-2a catalyzed allylic sub-
stitution reaction of 1,3-diphenyl-2-propenyl acetate was
also investigated. As shown in Table 1, CH Cl and
CH
3
Ac
2
O
Ph
Et
50-95%
2
PCl
NHMe
2
2
MeNH2
0%
3
N
CH CN are effective solvents for the allylic substitution
3
9
reaction, and enantioselectivities of 88.6% and 86.1% ee
were observed, respectively (entries 5 and 6). The best
result (91.8% ee) was achieved when toluene was
employed as solvent (entry 7).
4
SR
Fe
CH3
PPh
2
N
Me
3
Under the optimized reaction conditions: [Pd(g -
C H )Cl] (2 mol %); 2 (4.2 mol %), dimethyl malonate
3
5
2
2
(
3.0 equiv), BSA (3.0 equiv), and Zn(OAc) (2.0 mol %)
2
Scheme 1. Synthesis of the ferrocenyl N-P/S ligands 2.
in toluene at room temperature, the effectiveness of
other ferrocenyl phosphinamidites was tested using
1
,3-diphenyl-2-propenyl acetate as substrate. Our results
commercially available chiral Ugi’s amine,15 diastereo-
in Table 2 show that 2b and 2c bearing bulky R groups
selective ortho-lithiation using sec-BuLi/Et O, followed
t
2
(
Bu and Ph) are effective ligands for the Pd-catalyzed
allylic substitution using diethyl malonate with ca.
3% ee being attained. Apparently, the bulkier thioether
groups would necessitate longer reaction time (up to
20 min) albeit with improved enantioselectivities.
t
by quenching with disulfides (R = Et, Bu, Ph) afforded
the 1,2-disubstituted ferrocenyl amines 3a–c in 60–90%
9
1
6
yields. Treatment of 3 with Ac O and methylamine
2
furnished the ferrocenyl methylamine 4 in >90% yield.
The ferrocenylamine was then converted to the phosphi-
namidite 2 (50–95% yield) by phosphinylation using
1
1
7
Table 2. A study of influence of the thioether group of (S,R
FerroNPS ligands 2 on Pd-catalyzed AAA reaction
p
)-
Et N and Ph PCl.
3
2
a
c
When 1,3-diphenyl-2-propenyl acetate (0.5 M solution)
was treated with dimethyl malonate (3 equiv) in toluene
Entry
Ligand
Concn
(M)
Time
(min)
Yield
(%)
ee (%)
b
containing LiOAc as an additive (2 mol %), BSA
1
2
3
2a (R = Et)
2b (R = Bu)
2c (R = Ph)
0.5
45
90
120
97
94
94
91.8 (R)
92.7 (R)
93.5 (R)
3
t
(
3 equiv), [Pd(g -C H )Cl] (2 mol %) and (S,R )-Ferro-
3
5
2
p
NPS-Et 2a (4.2 mol %) at room temperature, the alkyl-
ated product was produced in >99% conversion and
a
3
Reaction conditions: [Pd(g -C
(
3
H
5
)Cl]
2
(2 mol %), ligand
2
8
1
7.9% ee based on chiral HPLC analysis (Table 1, entry
). For the asymmetric substitution of 1,3-diphenyl-2-
4.2 mol %), dimethyl malonate (3.0 equiv), BSA (3.0 equiv),
Zn(OAc) (2.0 mol %), and toluene as solvent at room temperature.
2
b
c
propenyl acetate, using NaOAc or KOAc as an additive
Isolated yield.
The % ee value was determined by HPLC on a Chiralpak AD
1.0 mL/min, n-Hex/ PrOH = 95:5).
i
(
p
Table 1. Pd-catalyzed asymmetric allylic alkylation using (S,R )-
FerroNPS-Et 2a as a chiral ligand with an addition of metal acetate
as an additive in various solvents
Having achieved enantioselective C–C bond formation
using the Pd-2a catalyzed allylic substitution reaction,
we also evaluated the ferrocenyl phosphinamidite
ligands for analogous C–N bond formation. Treatment
of 1,3-diphenyl-2-propenyl acetate (0.25 M) with benzyl-
a
OAc
Ph
CH(CO Me)2
3
2
[
η -C H PdCl] , 2a
3
5
2
*
Ph
CH
2
(CO
2
Me)
2
, BSA
Ph
Ph
3
additive, r.t.
amine (3 equiv) in ethyl acetate containing [Pd(g -
C H )Cl] (2 mol %) and (S,R )-FerroNPS-Et 2a
b
c
3
5
2
p
Entry Additive
Solvent Time (h) Conv. (%)
ee (%)
(4.2 mol %) at room temperature, afforded the product
1
2
3
4
5
6
7
LiOAc
NaOAc
KOAc
THF
12
>99
>99
>99
>99
>99
>99
>99
87.9 (R)
86.6 (R)
86 (R)
90.2 (R)
88.6 (R)
86.1 (R)
91.8 (R)
allyl amine in 98% yield and 89.1% ee. Similarly, other
ferrocenyl ligand derivatives 2b and 2c were also found
to effect the allylic amine substitutions with enantio-
selectivities of 91.5% and 81.7% ee, respectively (Table 3).
Zn(OAc)
2
CH
CH
2
Cl
CN
2
3
Toluene
3
. Conclusion
a
3
Reaction conditions: [Pd(g -C
(
(
3
H
5
)Cl]
4.2 mol %), dimethyl malonate (3.0 equiv), BSA (3.0 equiv), additive
2.0 mol %), and 0.5 M of concentration, room temperature.
2
(2 mol %), ligand
2
In conclusion, we have successfully developed a new
class of easily accessible ferrocene-based 1,2-disubsti-
tuted phosphinamidite-thioether ligands derived from
Ugi’s amine. These ferrocenyl P/S ligands have been em-
ployed for Pd-catalyzed asymmetric allylic alkylation
b
c
1
The conversion was determined by H NMR analysis of the crude
reaction mixture.
The % ee value was determined by HPLC on a Chiralpak AD column
i
(
1.0 mL/min, n-Hex/ PrOH = 95:5).

F. L. Lam et al. / Tetrahedron: Asymmetry 17 (2006) 497–499
499
Table 3. The results of Pd-catalyzed asymmetric allylic amination
3. Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346,
a
using (S,R
p
)-FerroNPS 2 as chiral ligand
497–537.
4
. (a) Selvakumar, K.; Valentini, M.; Worle, M.; Pregosin, P.
S.; Albinati, A. Organometallics 1999, 18, 1207–1215; (b)
Pretot, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37,
OAc
NHBn
[
η3-C H PdCl] , 2
3
5
2
*
2
BnNH , EA, r.t.
Ph
Ph
Ph
Ph
3
23–325.
5. Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237–2240.
. (a) Albinati, A.; Pregosin, P. S.; Wick, K. Organometallics
996, 15, 2419–2421; (b) Selvakumar, K.; Valentini, M.;
Pregosin, P. S.; Albinati, A. Organometallics 1999, 18,
591–4597.
b
c
Entry Ligand Concn (M) Time (h) Yield (%)
ee (%)
6
1
2
3
2a
2b
2c
0.25
3.5
48
75
98
86
92
89.1 (S)
91.5 (S)
81.7 (S)
1
0.1 (THF)
0.1
4
a
3
Reaction conditions: [Pd(g -C
4.2 mol %), benzylamine (3.0 equiv), and EA as solvent at room
3
H
5
)Cl]
2
(2 mol %), ligand
2
7. (a) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael,
F. E.; Gagne, M. R. J. Org. Chem. 1999, 64, 2994–2995;
(b) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael,
F. E.; Gagne, M. R. J. Am. Chem. Soc. 2000, 122, 7905–
7920.
(
temperature.
Isolated yield.
b
c
The % ee value was determined by HPLC on an OJ-H column
0.4 mL/min, n-Hex/ PrOH = 85:15).
i
(
8. Mancheno, O. G.; Priego, J.; Cabrera, S.; Arrayas, R. G.;
Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679–
3
686.
and amination, and excellent enantioselectivities and
chemical yields were observed. Further investigation of
other catalytic asymmetric reactions with these ferro-
cenyl N-P/S ligands is currently underway.
9
. Cabreba, S.; Arrayas, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2004, 43, 3944–3947.
0. Mancheno, O. G.; Arrayas, R. G.; Carretero, J. C. J. Am.
Chem. Soc. 2004, 126, 456–457.
1. Cabreba, S.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem.
Soc. 2005, 127, 16394–16395.
2. Cabreba, S.; Arrayas, R. G.; Alonso, I.; Carretero, J. C.
J. Am. Chem. Soc. 2005, 127, 17938.
3. (a) Colacot, T. J. Chem. Rev. 2003, 103, 3101–3118; (b)
Dai, L.; Tu, T.; You, S.; Deng, W.; Hou, X. Acc. Chem.
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Asymmetry 2004, 15, 2273–2278.
1
1
1
1
Acknowledgments
We thank the UGC Areas of Excellence Scheme (AoE/
P-10/01) and The Hong Kong Polytechnic University
(
ASD) for financial support.
1
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