New chiral ferrocenyl amidophosphine ligand for remarkable improvement of enantioselectivities in copper-catalyzed addition of diethylzinc to N-sulfonylimines

Article abstract of DOI:10.1016/j.tetlet.2005.05.143

(S)-N-Ferrocenoyl-2-[(diphenylphosphino)methyl]-pyrrolidine 3 was conveniently prepared from commercially available l-proline and ferrocenecarboxylic acid. In the presence of a catalytic amount of chiral ligand 3 (4 mol %) and Cu(OTf)₂ (3 mol %), the asymmetric addition of diethylzinc to N-sulfonylimines was achieved in 57-99% yield with up to 88% ee.

Full text of DOI:10.1016/j.tetlet.2005.05.143

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5413–5416
New chiral ferrocenyl amidophosphine ligand for
remarkable improvement of enantioselectivities in
copper-catalyzed addition of diethylzinc to N-sulfonylimines
Min-Can Wang,* Cui-Lian Xu, Yu-Xi Zou, Hong-Min Liu* and De-Kun Wang
Department of Chemistry, Zhengzhou University, Zhengzhou, Henan 450052, China
Received 21 February 2005; revised 26 May 2005; accepted 30 May 2005
Available online 23 June 2005
Abstract—(S)-N-Ferrocenoyl-2-[(diphenylphosphino)methyl]-pyrrolidine 3 was conveniently prepared from commercially available
L-proline and ferrocenecarboxylic acid. In the presence of a catalytic amount of chiral ligand 3 (4 mol %) and Cu(OTf)2 (3 mol %),
the asymmetric addition of diethylzinc to N-sulfonylimines was achieved in 57–99% yield with up to 88% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
Much efforts have been made in the efficient asymmetric
synthesis of chiral amines, which are subunits of some
biologically active compounds or important resolving
reagents.1 Asymmetric addition of organometallic
reagents to imines has been investigated in recent years.2
Enantioselective addition of dialkylzinc to imines is one
of the most efficient approaches to chiral amines. Many
chiral b-amino alcohols have been designed to catalyze
the dialkylzinc addition in the presence of stoichiometric
amounts of ligands while high enantioselectivities were
attained.3 But one drawback of this system is, with cat-
alytic amount of ligand, low reactivity and enantioselec-
tivity were observed. This is in great contrast to the
chiral amino alcohol-catalyzed asymmetric alkylation
of aldehydes with dialkyzinc reagents, which becomes
an effective and general method.4 Therefore, the asym-
metric addition of organometallic reagents to imines in
the presence of catalytic amounts of chiral ligands is
challenging. Recent studies in this field have revealed
that some chiral complexes, including copper–amido-
phosphine,5 rhodium–monophosphine,6 zirconium–pep-
tidic Schiff base,7 allylpalladium complexes,8 zinc
complex,9 copper–Me–DuPHOS (or Boz–PHOS),10
copper–N-(binaphthyl-2-yl)thiophosphoramide, etc.11
catalyze the addition of dialkylzinc to imines bearing
different protected groups with high enantioselectivities.
In the course of our ongoing studies on the synthesis and
application of novel ferrocenyl ligands containing a rigid
cyclic skeleton,12 that is considered to be the determin-
ing factor for the effectiveness of these ligands in
asymmetric catalytic reactions. We found that the
introduction of a ferrocenyl unit on the nitrogen atom
of aziridine-based skeleton led to a remarkable improve-
ment in the enantioselectivity when used as a catalyst in
the addition of diethylzinc to benzaldehyde.12a,b In
order to apply this idea to other chiral ligands and cat-
alytic systems, we decided to use L-proline as a chiral
source to synthesize chiral amidophosphine ligands
bearing ferrocenyl group and use the ligands in asym-
metric catalysis. Herein, we present our preliminary
results on the asymmetric addition of diethylzinc to
N-sulfonylimines by means of catalytic amounts of these
novel chiral ligands.
The chiral ligands 3–5 were readily obtained from the
reaction of ferrocenecarboxylic acid with L-proline.
The preparation of 3–5 is outlined in Scheme 1. The
reaction of ferrocenecarboxylic acid 1 with oxalyl chlo-
ride in CH2Cl2 gave ferrocenyl chloride, which was then
combined with (S)-prolinol in the presence of Et3N to
give (S)-ferrocenoyl prolinol 2 in 69% yield.13 The treat-
ment of 2 with p-TsCl in the presence of pyridine affor-
ded (S)-ferrocenoyl prolinol tosylate in 72% yield, which
was further substituted by NaPPh2 to give the ligand 3
in 84% yield14 according to the reported procedure.15
The treatment of 2 with ClPPh2 directly in the presence
of Et3N16 led to ligand 4 in 87% yield.17 Ligand 3 was
*
Corresponding authors. Tel.: +86 371 67769024; fax: +86 371
67769024 (M.-C.W.); e-mail: wangmincan@zzu.edu.cn
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.143

5414
M.-C. Wang et al. / Tetrahedron Letters 46 (2005) 5413–5416
Table 1. The asymmetric diethylzinc addition to 6a catalyzed by
copper-complexes of 3–5a
O
C
O
C
COOH
N
N
c, d
a, b
Fe
Fe
Ts
Fe
Ts
N
HN
Cu(OTf)2-ligand
toluene
OH
PPh2
Et2Zn
+
2
1
3
Ar
Ar
H
Et
e
f
O
C
7a
6a
N
N
Entry Ligand
loading (%) (%)
Cu(OTf)2 Temperature Time Yieldb eec
Fe
Fe
(°C)
(h)
OPPh2
PPh2
1
3 (2)
4 (2)
5 (2)
3 (1)
3 (4)
3 (7)
3 (3)
3 (3)
3 (3)
3 (4)
3 (4)
2
2
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
ꢀ5to 0
1512
12
88
86
92
84
94
95
86
93
70
84
1
4
5
2
12
12
12
12
12
12
12
12
3
2
21
72
86
Scheme 1. Synthesis of ligands 3–5. Reagents and conditions: (a)
(COCl)2, CH2Cl2; (b) (S)-prolinol, Et3N, CH2Cl2; (c) p-TsCl, Py,
CH2Cl2; (d) NaPPh2, THF–dioxane; (e) ClPPh2, Et3N, THF; (f)
LiAlH4, THF.
4
3
5
3
6
3
86
7
10
5
80
85
77
8
9
1
reduced by LiAlH4 in THF to afford ligand 5 in 79%
yield.18
10
11
3
84
62
3
ꢀ71524 885
a The reactions were performed at a 0.2 mmol scale. The ratio of Et2Zn
to imine was 3:1.
b Isolated yield.
Initially, in order to find out the best ligands and an
optimal procedure, we chose the diethylzinc addition
to N-(benzylidene)-p-methylbenzenesulfonamide (N-
sulfonylimine) 6a as a model reaction in the presence
of 2 mol % of ligands 3–5 and Cu(OTf)2 under different
conditions. The enantiomeric purity of product 7a was
determined by HPLC analysis with a chiral stationary
phase column (Daicel Chiralcel OD, hexane/i-PrOH
(10:1), 254 nm, 0.7 mL/min). The results are summarized
in Table 1.
c The ee was determined by HPLC with Daicel Chiralcel OD: eluent,
10% 2-propanol in hexane. The absolute configuration of 7a was
assigned as S by comparing retention time of HPLC with the liter-
ature value.
vs 5) when 3 mol % of Cu(OTf)2 was used. We
attempted to further increase the ligand loading to
7 mol % for higher enantioselectivity, but there was no
significant change in either yield or enantioselectivity.
When 3 mol % of the chiral ligand 3 was employed
(Table 1, entries 7–9), 5mol % of Cu(OTf) 2 gave better
ee (85%). So, the combination of 4 mol % of chiral ligand
and 3 mol % of Cu(II) salt seemed the most suitable cat-
alyst for the alkylation of imines. Then, we investigated
the effect of reaction temperature on enantioselectivity.
Increasing the reaction temperature from ꢀ5–0 °C to
15 °C led to a dramatic decrease in the enantioselectivity
from 86% to 62% (Table 1, entry 5vs 10), while lowering
the reaction temperature from ꢀ5–0 °C to ꢀ15 °C
resulted in an slight enhancement in the enantioselectiv-
ity from 86% to 88% (Table 1, entries 5and 11), but with
a remarkable decrease in yield from 94% to 57%.
As seen from Table 1, the first important conclusion was
the high yield and significant enantioselectivities (Table
1, entries 1–3). For example, when chiral ligand 3 was
employed, the addition product 7a was obtained in
84% ee (Table 1, entry 1). But under the same condition,
racemic product was obtained when ligand 4 was used
(Table 1, entry 2). Ligand 5 also gave poor ee (Table
1, entry 3). These results indicate that a ligand is in-
volved in the addition reaction. Furthermore, a compari-
son of the enantionselectivities of ligand 3 (88% ee) with
those of 4 (1% ee) and 5 (21% ee) suggests that the bite
angle of ligand to transition metal is responsible for the
enantioselectivity. A comparison of entries 1 and 3 in
Table 1 also indicates that the presence of a conjugating
carbonyl in the Cp system facilitates the formation and
increases the stability of a zinc cuprate–oxygen phos-
phine complex, which is the reactive intermediate of
1,4-conjugate addition.5
Recently, Tomioka et al. reported the same type of chi-
ral ligands 8 for the addition of diethylzinc to N-(benzyl-
idene)-p-methylbenzenesulfonamide (N-sulfonylimine)
6a with low enantioselectivities (51–65% ee).5b Compari-
son of our results (88% ee) with those of Tomioka et al.
demonstrate that the introduction of a ferrocenyl group
into the chiral amidophosphine ligands results in a
remarkable improvement in the enantioselectivity.
These results also suggest that the hindrance of rigid,
bulky ferrocenyl unit plays an important role in the
Compound 3 was chosen as the best chiral ligand for
further optimization (Table 1, entries 4–11). We first
examined the effects of the ratio of ligand 3 to Cu(OTf)2
on enantioselectivity (Table 1, entries 1, 4–9). Increasing
chiral ligand loading from 1 to 4 mol % led to a signifi-
cant improvement in enantioselectivity (Table 1, entry 4
O
C
O
C
R
R = PhCH2,
2,4,6-Me3C6H2CH2.
N
N
R = Me, Et, n-Bu,
n-Oct, 1-Ad, t-Bu
t-Bu
R
R
ee: 90-93%
ee: 51-65%
PPh2
PPh2
9
8

M.-C. Wang et al. / Tetrahedron Letters 46 (2005) 5413–5416
5415
addition of diethylzinc to N-sulfonyl.11a,19 Efforts are
underway to extend this catalytic system to other asym-
metric C–C bond forming processes, which will be
reported in due time.
Table 2. The enantioselective addition of diethylzinc to various
N-sulfonylimines 6a
Ts
Ts
H
HN
N
Cu(OTf)2-ligand 3
toluene, -5-0 oC
Et2Zn
+
*
Ar
Ar
Et
7a-l
6a-l
Acknowledgements
Entry
Ar
C6H5
Imine
Yieldb (%)
eec (%)
1
2
3
4
7a
7b
7c
7d
94
93
99
81
86
81
85
81
We are grateful to the National Natural Sciences Founda-
tion of China (NNSFC: 20172047), Henan Outstanding
Youth Program 2001, and the Education Department
of Henan Province for the financial supports.
2-MeOC6H5
3-MeOC6H5
4-MeOC6H5
O
5
7e
98
84
O
4-MeC6H5
6
7f
7h
7i
79
97
82
79
81
References and notes
7
2-ClC6H5
3-ClC6H5
4-ClC6H5
3-BrC6H5
2-Furyl
8
97
9
7j
8582
94
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to N-sulfonyl imines when used in catalytic amounts.
In conclusion, we have demonstrated three new pyrrol-
idinyl-based chiral ferrocenoylphosphine or ferrocenyl-
phosphine ligands which were conveniently synthesized
from commercially available ferrocenecarboxylic acid
and L-proline. Among them, ligand 3–Cu(OTf)2 proved
to be an efficient chiral catalyst in the asymmetric addi-
tion of diethylzinc to N-sulfonylimines, giving the chiral
amine product in good to excellent yields and high
enantioselectivities with catalytic amount of catalyst
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M.-C. Wang et al. / Tetrahedron Letters 46 (2005) 5413–5416
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4.31–4.33 (m, 1H, NCH), 4.18–4.72 (m, 9H, FcH). HRMS
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1H, NCHH), 3.82–3.84 (m, 1H, NCHH), 4.05–4.08 (m,
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20
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2H, CHHPPh2, NCHH), 2.25–2.35 (m, 1H, NCHH),
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20
14. Compound 3: mp 114.8–116.0 °C, ½aꢁD ꢀ38.6 (c 0.8,
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1H, CH2CHH), 1.85–2.10 (m, 3H, CH2CHH, CH2CH2),