A new type of ferrocene-based phosphine-tert-butylsulfinamide ligand: Synthesis and application in asymmetric catalysis

Article abstract of DOI:10.1039/c5ra03010b

A new type of ferrocene-based phosphine-tert-butylsulfinamide ligand has been synthesized and applied to the enantioselective formation of C-C and C-N bonds. The palladium complex derived from ligand 4a was an efficient catalyst in asymmetric allylic substitution of several substrate types. Enantioselectivites with the difficult substrate 3-acetoxycyclohexene of up to 91% ee are achieved.

Full text of DOI:10.1039/c5ra03010b

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A new type of ferrocene-based phosphine-tert-
butylsulfinamide ligand: synthesis and application
in asymmetric catalysis†
Cite this: RSC Adv., 2015, 5, 35888
Received 17th February 2015
Accepted 14th April 2015
*
Jiangwei Ma, Chuang Li, Dongxu Zhang, Yang Lei, Muqiong Li, Ru Jiang
*
and Weiping Chen
DOI: 10.1039/c5ra03010b
www.rsc.org/advances
A
new type of ferrocene-based phosphine-tert-butylsulfinamide butanesulnamides also provides excellent opportunities for
ligand has been synthesized and applied to the enantioselective the development of N-sulnyl-based ligands for asymmetric
formation of C–C and C–N bonds. The palladium complex derived catalysis.6
from ligand 4a was an efficient catalyst in asymmetric allylic substi-
tution of several substrate types. Enantioselectivites with the difficult rare.7 Verdaguer reported ligand 1 for the intermolecular
However, the ligands containing a sulnamide moiety are
substrate 3-acetoxycyclohexene of up to 91% ee are achieved.
asymmetric Pauson–Khand reaction and ligand 2 for asym-
metric hydrogenation (Fig. 1).8 These ligands coordinate readily
to rhodium, palladium and other metals to give either P,O or P,S
bidentate coordination.9 Recently, ligand 3 was developed and
applied in the Pd-catalyzed asymmetric allylic alkylation by
Bolm.10 Very recently, Zhang described Ming-Phos for the
enantioselective gold-catalyzed cycloaddition reaction of 2-(1-
alkynyl)-alk-2-en-1-ones with nitrones.11 As a part of our
continuous research on the development of ferrocene-based
chiral ligands and catalysts,12 we are interested in exploring
the potential of ferrocene-based bidentate ligands containing
tert-butylsulnamide moiety. Herein, we describe the synthesis
of ferrocene-based phosphine-tert-butylsulnamide ligands 4
and the preliminary results of their palladium complexes cata-
lyzed asymmetric allylic substitution reaction.
Phosphine-tert-butylsulnamide 4 was easily synthesized
from (R)-Ugi's amine 5 in three steps (Scheme 1). Highly dia-
stereoselective ortho-lithiation of 5 followed by treatment with
ClPR2 gave compound 6, which was transformed into amino-
phosphine 7 by reaction with Ac2O, and then ammonolysis with
a large excess of ammonia or amine.13 Ligand 4a–g were
obtained by sulnylation of the lithium salts of 7 (formed in situ
by deprotonation of 7 with n-BuLi) using an enantiopure tert-
butanethiosulnate. These ligands were characterized by 1H
NMR, 13C NMR, 31P NMR and mass spectrometry.
Chiral ligands have been considered one of the most impor-
tant topics in asymmetric catalysis over the last three decades
owing to their fruitful applications in asymmetric synthesis.1
Among the thousands of chiral ligands prepared, bidentate
ligands have become the most powerful tool in metal-catalyzed
asymmetric processes since chelation provides the rigidity
required to rmly allocate the chiral information around the
metal center. Usually, the chirality of most bidentate ligands
resides in the carbon backbone. However, some have a chiral
phosphorus or sulfur center, and few have both a chiral scaf-
fold and a chiral phosphorus or sulfur center. The ligands with
chirality at the metal-coordinating atom, which bring the
chiral information into the closest possible proximity to the
catalytic center, might increase enantioselectivities of the
catalytic transformations that the catalyst is mediating.
Indeed, P-stereogenic bidentate diphosphine ligands are
extremely procient in asymmetric transformations.2
However, the synthesis of chiral-phosphorus ligands is oen
complex and difficult. In contrast, the preparation of chiral
sulfur compounds is more convenient and several chiral
sulfoxides and sulnamides are commercially available.3 Pio-
neered by Ellman,4 both enantiomers tert-butylsulnamide is
now available in large amounts and is used as a sacricial
chiral auxiliary in a wide range of synthetic processes.5 The
ease of synthesis, stability, resident chirality, and potential for
metal coordination of the S, N and O atoms of N-tert-
School of Pharmacy, Fourth Military Medical University, 169 Changle West Road,
Xi'an, 710032, PR China. E-mail: jiangru@fmmu.edu.cn; wpchen@fmmu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra03010b
Fig. 1 Known phosphine-tert-butylsulfinamide ligands.
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Table 2 The effect of solvents on the asymmetric allylic alkylation
using ligand 4aa
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
CH2Cl2
THF
Toluene
ClCH2CH2Cl
Dioxane
Et2O
63
65
73
66
63
29
72
55
49
77
55
73
65
55
72
41
Scheme 1 Synthesis of ligand 4.
We rst tested the ligands in the Pd-catalyzed asymmetric
allylic alkylation of racemic (E)-1,3-diphenylallyl acetate 8a with
dimethyl malonate 9 as a model reaction using standard
conditions (Table 1). The results indicated that the chiralities of
ferrocenyl moiety in the ligands play the decisive role in the Pd-
catalyzed asymmetric allylic alkylation, giving (R)-10a (Table 1,
entries 1–6). While the carbon-centred chirality and the planar
chirality of ferrocene scaffold are the main governing factors,
the sulfur-centred chirality of sulnamide moiety is also
important, and (RC,SFc,RS)-4 are the ligands with the matched
chiralities (entry 1 vs. 6).
Notably, when replacement of NH of sulnamide moiety with
N-Me, both the activity and enantioselectivity decreased
dramatically, suggesting that a sterically bulky substituent is
disfavoured or a hydrogen-bonding donor is essential for the
stereoinduction (Table 1, entries 1 vs. 2, 6 vs. 7). With regard to
the effect of the P-substituents, the aryl groups were highly
benecial in terms of enantioselectivity and catalytic activities
(Table 1, entries 1, 3, 4 vs. 5). But the bulky aryl groups had a
deleterious effect on enantioselectivity (Table 1, entries 1 vs. 3, 4).
To further improve the chemical yield and enantioselectivity,
we optimized the reaction conditions. The effect of solvent,
DMF
CH3CN
a
The reaction was conducted with rac-(E)-1,3-diphenylallyl acetate 8a
(0.4 mmol), dimethyl malonate 9 (1.2 mmol) [Pd(C3H5)Cl]2 (0.008
mmol), 4a (0.024 mmol), BSA (1.2 mmol), LiOAc (0.034 mmol) in
b
c
solvent at 25 ꢀC. Isolated yields. Determined by chiral HPLC
analysis using a chiral column (Chiralcel AD-H column, hexane/i-
propanol ¼ 80 : 20).
reaction temperature, base and additives on the catalytic
activity and enantioselectivity were investigated using 4a as the
ligand. As shown in Table 2, the solvent was observed to play a
crucial role, and THF proved to be superior.
Table 3 Further optimization of reaction conditionsa
Temperature
Entry Base
Additive (mol%) (ꢀC)
Yieldb (%) eec (%)
Table 1 Screening of the ligands in asymmetric allylic alkylationa
1
2
3
4
5
6
7
8
None
n-BuLi None
NaH
KOH
Cs2CO3 None
K2CO3
BSA
BSA
BSA
BSA
BSA
BSA
BSA
BSA
BSA
BSA
None
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40
0
15
77
65
70
59
40
70
69
66
60
62
45
55
60
64
30
43(R)
11(R)
12(S)
33(S)
29(S)
rac
77(R)
81(R)
82(R)
71(R)
51(R)
67(R)
74(R)
89(R)
84(R)
75(R)
None
None
None
LiOAc (9)
LiOAc (6)
LiOAc (3)
NaOAc (9)
KOAc (9)
CsOAc (9)
AgOAc (9)
None
Entry
Ligand
Yieldb (%)
eec (%)
9
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
65
34
65
52
35
75
36
77(R)
5(R)
10
11
12
13
14
15
16
67(R)
71(R)
52(R)
27(R)
9(S)
None
None
4g
a
a
The reaction was conducted with rac-(E)-1,3-diphenylallyl acetate 8a
The reaction was conducted with rac-(E)-1,3-diphenylallyl acetate 8a
(0.4 mmol), dimethyl malonate 9 (1.2 mmol) [Pd(C3H5)Cl]2 (0.008 (0.4 mmol), dimethyl malonate 9 (1.2 mmol), [Pd(C3H5)Cl]2 (0.008
mmol), ligand 4 (0.024 mmol), BSA (1.2 mmol), LiOAc (0.034 mmol) mmol), 4a (0.024 mmol), base (1.2 mmol), additive in THF 25 ꢀC.
b
c
b
c
in THF at 25 ꢀC. Isolated yields. Determined by chiral HPLC
Isolated yields. Determined by chiral HPLC analysis using a chiral
analysis using a chiral column (Chiralcel AD-H column, hexane/i- column (Chiralcel AD-H column, hexane/i-propanol ¼ 80 : 20). The
propanol 80 : 20). Absolute conguration was assigned by absolute conguration was determined by comparing the specic
¼
comparing the optical rotation values with those reported in the rotation with a literature value.
literature.
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Table 4 Scope of asymmetric allylic alkylation using ligand 4aa
Encouraged by these results, our attention focused on inves-
tigating the scope of this catalytic system, various nucleophiles
and substrates were screened. When CH2(CO2Et)2 was used as
the nucleophile instead of CH2(CO2Me)2, the yield and enantio-
selectivity were maintained (Table 4, entry 2). But bulky nucleo-
phile decreased the ee value of product 10 (Table 4, entry 3).
Employing acetylacetone as nucleophile led to a signicant drop
in the enantioselectivity and chemical yield (Table 4, entry 4). On
the other hand, diarylallyl acetate 8 bearing either the electron-
donating or electron-withdrawing substituents on the aromatic
ring underwent the reaction smoothly to give the desired prod-
ucts in good levels of enantioselectivities (Table 4, entries 5, 6).
To further study the potential of ligand 4a, we also tested it in
the asymmetric allylic alkylation of more challenging unhin-
dered cyclic substrate 11 and unsymmetrical disubstituted
linear substrates 13, 15 (Scheme 2). To the best of our knowl-
edge, few catalysts were efficient for asymmetric allylic alkyl-
Entry
Ar
NuH
Yieldb (%)
eec (%)
1
2
3
4
5
6
C6H5 (8a)
C6H5 (8a)
C6H5 (8a)
C6H5 (8a)
4-MeC6H4 (8b)
4-ClC6H4 (8c)
CH2(COOMe)2
CH2(COOEt)2
CH(CH3)(COOMe)2
Acetylacetone
CH2(COOMe)2
CH2(COOMe)2
62
65
55
41
55
59
89
88
76
29
62
78
a
The reaction was conducted with rac-(E)-1,3-diarylallyl acetate 8 (0.4
mmol), NuH (1.2 mmol), [Pd(C3H5)Cl]2 (0.008 mmol), 4a (0.024
b
mmol), BSA (1.2 mmol) in solvent at 25 ꢀC. Isolated yields.
c
Determined by chiral HPLC analysis using a chiral column. (Entry 1:
Chiralcel AD-H column, hexane/i-propanol ¼ 80 : 20; entry 2: Chiralcel
AD-H column, hexane/i-propanol ¼ 93 : 7; entry 3: Chiralcel AD-H +
AD-H column, hexane/i-propanol ¼ 99 : 1; entry 4: Chiralcel AD-H
column, hexane/i-propanol ¼ 99 : 1; entry 5: Chiralcel AD-H column,
hexane/i-propanol ¼ 94 : 6; entry 6: Chiralcel AD-H column, hexane/i-
propanol ¼ 85 : 15).
ation
of
these
substrates.10,15
Importantly,
high
enantioselectivity (91% ee) was obtained in the allylic alkylation
of difficult substrate 11. For substrates 13 and 15, the catalytic
system showed dissatisfactory regioselectivity, but ee value of
each isomer were moderate to high.
Having achieved enantioselective C–C bond formation, we
also evaluated the chiral phosphine-tert-butylsulnamide
ligands in a C–N bond formation reaction. In the presence of
ligand 4, rac-(E)-1,3-diphenylallyl acetate 8a was reacted with
benzylamine under conditions similar to those of alkylation
described above. Ligand 4a and THF were also the best ligand
and solvent, respectively. Similarly, BSA was the best base, but
15 mol% NaOAc was necessary for the best enantioselectivity
(Table 5, entry 10). Screening of various palladium precursors
indicated that [Pd2(dba)3]CHCl3 was superior to [Pd(C3H5)Cl]2
and Pd2(dba)3 (Table 5, entries 6 vs. 2, 4). With the reaction
conditions optimized, other amines were also examined in this
reaction. Moderate enantioselectivities were also obtained
(Table 5, entries 11, 12).
It is noteworthy that the base has a pronounced inuence on
the catalytic performance (Table 3). The reaction proceeded
quickly in the presence of strong bases, such as n-BuLi, NaH, or
KOH, but the enantioselectivities were poor (Table 4, entries 2–
4). When N,O-bis(trimethylsilyl)acetamide (BSA) was used as a
base and a catalytic amount of salt as an additive,14 enantiose-
lectivities were improved signicantly, while chemical yield
decreased slightly (Table 3, entries 7–13). Interestingly, the
highest enantioselectivity were achieved in 89% ee when BSA
was used as a base in the absence of salt additives (Table 3, entry
14). Examination of the temperature effects revealed that 25 ꢀC
was optimal for the reaction (Table 3, entries 14 vs. 15, 16).
Scheme 2 Asymmetric allylic alkylation of challenging substrates using ligand 4a.
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Table 5 Pd-catalyzed asymmetric allylic aminations using ligand 4aa
Entry
Pd
R1R2NH
Base
Additive (mol%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
[Pd2(dba)3]CHCl3
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Morpholine
None
BSA
None
BSA
None
BSA
BSA
BSA
BSA
BSA
BSA
BSA
None
NaOAc (9)
None
NaOAc (9)
None
NaOAc (9)
LiOAc (9)
KOAc (9)
NaOAc (6)
NaOAc (15)
NaOAc (15)
NaOAc (15)
47
31
53
40
32
43
40
55
40
45
72
16
9(R)
rac
37(R)
13(S)
17(R)
82(R)
43(R)
49(R)
65(R)
87(R)
55(R)
74(R)
9
10
11
12
p-Methoxy aniline
a
The reaction was conducted with rac-(E)-1,3-diphenylallyl acetate 8a (0.4 mmol), R1R2NH 17 (1.2 mmol), palladium precursor (0.008 mmol), 4a
b
c
(0.024 mmol), BSA (1.2 mmol) and additive in solvent at 25 ꢀC. Isolated yields. Determined by chiral HPLC analysis using a chiral column.
(Entries 1–10: Chiralcel AD-H column, hexane/i-propanol ¼ 90 : 10; entry11: Chiralcel OD-H column, hexane/i-propanol ¼ 90 : 10; entry12:
Chiralcel OD-H column, hexane/i-propanol ¼ 90 : 10). Absolute conguration was assigned by comparing the optical rotation values with those
reported in the literature.
A plausible mechanism for the asymmetric induction with carbon trans to phosphorus affording (R)-isomer (Fig. 2). Simi-
chiral phosphine-tert-butylsulnamide ligand 4a was proposed larly, the transition state 21 would be more stable than 22 to
on the basis of the stereochemical results obtained. A seven- provide (R)-isomer for the cyclic substrate 11.
membered chelated p-allylpalladium complex would be
formed by coordination of the phosphine and the sulnamide
to palladium. The W-type p-allyl complex 19 would be more
Conclusions
stable than the M-type complex 20, which has repulsive inter-
action between the two phenyl groups in substrate 8 with the t-
butyl group on the S atom and two phenyl groups on the P atom.
The nucleophile would preferentially attack the allylic terminal
A new type of ferrocene-based phosphine-tert-butylsulnamide
ligands have been synthesized and applied to the enantiose-
lective formation of C–C and C–N bond. The palladium complex
derived from ligand 4a was an efficient catalyst in asymmetric
allylic alkylation of symmetrical disubstituted linear substrates
(up to 89% ee), unsymmetrical disubstituted linear substrates
(up to 89% ee) and unhindered cyclic substrate (up to 91% ee).
For the asymmetric allylic amination, good stereoselectivities
were also obtained (up to 87% ee). Further studies focusing on
the modication of the ligands and applications in other cata-
lytic reactions are currently underway in our laboratory.
Acknowledgements
We thank the National Natural Science Foundation of China
(21272271, 21472240) and Natural Science Foundation of
Shannxi Province (2014JM2-8192) for nancial support.
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Fig. 2 Plausible transition state for the allylic alkylation using ligand 4a.
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