A CuII-N,P Oxazolinylferrocene Ligand Complex for the Asymmetric [3+2] 1,3-Dipolar Cycloaddition of Azomethine Ylide with Malonates

Article abstract of DOI:10.1002/cctc.201403048

A series of enantioselective pyrrolidine-2,4,4-tricarboxylate derivatives were synthesized by the [3+2] 1,3-dipolar cycloaddition of azomethine ylide with alkylidene malonates. By using 4 mol% of a Cu^II oxazolinylferrocene ligand complex and 10

Full text of DOI:10.1002/cctc.201403048

DOI: 10.1002/cctc.201403048
Communications
A CuII-N,P Oxazolinylferrocene Ligand Complex for the
Asymmetric [3+2] 1,3-Dipolar Cycloaddition of
Azomethine Ylide with Malonates
Li Dai, Di Xu, Li-Wei Tang, and Zhi-Ming Zhou*[a]
A series of enantioselective pyrrolidine-2,4,4-tricarboxylate de-
rivatives were synthesized by the [3+2] 1,3-dipolar cycloaddi-
tion of azomethine ylide with alkylidene malonates. By using
4 mol% of a CuIIÀN,P oxazolinylferrocene ligand complex and
10 mol% of a base, pyrrolidine analogues were obtained in
high yields (77–99%) and excellent enantioselectivities (up to
99% ee).
dipolar cycloaddition of azomethine ylides with nitroalkenes
catalyzed by CuI/imidazolium-tagged ferrocenyloxazolinephos-
phine (FimiOXAP), and obtained high yields and excellent
enantioselectivities.[13] Encouraged by our success, we envis-
aged that a series of easily prepared oxazolinylferrocene li-
gands could be applied to the asymmetric 1,3-dipolar cycload-
dition of azomethine ylides with alkylidene malonates.
We initially tested the CuI/FimiOXAP (1a, 10 mol%) catalyst
system in the reaction between glycine imino ester 2a, which
is the precursor to an azomethine ylide, and alkylidene malo-
nate 3a. The 1,3-dipolar cycloaddition reaction proceeded
smoothly and afforded product exo-4aa in 98% yield and
45.6% ee (Table 1, entry 1). We screened various N,O- and N,P-
ferrocene oxazoline ligands, which were considered to be suit-
able ligands for the reaction (Table 1, entries 2–9). The catalytic
activity of the N,P-ferrocene oxazoline ligands (1 f–1i) was su-
perior to that of the N,O-ferrocene oxazoline ligands (1b–1e).
When ligand 1h (Table 1, entry 8) was employed, better results
were achieved than with the other ligands (99% yield and
96.2% ee). Therefore, siloxane-substituted FOXAP ligand 1h
was selected as the chiral ligand for subsequent screening. Dif-
ferent AgI and CuI/CuII salts were investigated (Table 1, en-
tries 10–13). The AgOAc complex combined with 1h only af-
forded 81.2% ee. Fortunately, Cu(OAc)2·H2O afforded a quantita-
tive yield and the best enantiomeric excess (99.0% ee). Further-
more, in the reaction that utilized the CuII/1h catalyst, 4 mol%
of the catalyst afforded a comparable yield and enantiomeric
excess (Table 1, entry 14). However, the ee value of 4aa de-
creased to 96.0% when the catalyst loading was reduced to
2.5 mol% (Table 1, entry 15).
Over the past several decades, the catalytic enantioselective
1,3-dipolar cycloaddition of azomethine ylides with dipolaro-
philes has been greatly improved.[1] In 1991, Allway and Grigg
first reported the use of stoichiometric amounts of CoCl2 (or
MnBr2) and an ephedrine derivative as a chiral catalytic system
for the enantioselective cycloaddition of azomethine ylides
with methyl acrylate.[2] Recently, diverse chiral complexes con-
taining ZnII,[3] AgI,[4] CuI/CuII,[5] AuI,[6] NiII,[7] CaII,[8] and various or-
ganocatalysts[9] have been investigated as catalysts in asym-
metric [3+2] 1,3-dipolar cycloadditions. In addition, the asym-
metric [6+3][10] and [3+3][11] cycloaddition of azomethine ylides
has been reported to form medium-sized N-heterocycles.
However, alkylidene malonates, which have been employed
as Michael acceptors in conjugate additions, have rarely been
applied as dipolarophiles in asymmetric 1,3-dipolar cycloaddi-
tions.[12] Wang and co-workers first reported the asymmetric
1,3-dipolar cycloaddition of azomethine ylides with alkylidene
malonates catalyzed by a AgI/TF-BiphamPhos system.[12a] Very
recently, Furukawa and co-workers described the application
of a bifunctional AgI/ThioClickFerrophos complex in an asym-
metric 1,3-dipolar cycloaddition, which afforded high yields
and enantioselectivities.[12b] Deng and co-workers subsequently
employed a 10 mol% N,O-ligated copper complex, resulting in
high enantioselectivities.[12c] The high cost of the silver salt and
the large loading of the copper catalyst warrant the search for
more-efficient catalytic systems for this type of cycloaddition.
To the best of our knowledge, the easily prepared ferroceny-
loxazolinephosphine (FOXAP) ligands have not been applied as
ligands in the cycloaddition of azomethine ylide with malo-
nates to date. We have previously studied the asymmetric 1,3-
Encouraged by the aforementioned results, we investigated
the effects of the reaction conditions on the asymmetric 1,3-di-
polar cycloaddition. Screening available solvents revealed that
CH2Cl2 was the appropriate solvent in terms of both yield and
enantioselectivity (Table 1, entries 14 and 17–21). The effect of
base was also probed. The desired product was not formed
when KOAc or CsOAc was used (Table 1, entries 22 and 23).
The enantioselectivity of cycloadduct 4aa decreased some-
what upon switching from N,N-diisopropylethylamine (DIPEA)
to Cs2CO3 (Table 1, entry 24, 95.4% ee). To our surprise, the
enantioselectivity increased (99.2% ee) when K2CO3 was used
(Table 1, entry 25). Compared with the 2 equivalents of K2CO3
in the work of Deng and colleagues that uses a 1,3-dihydroimi-
dazole-based N,O-bidentate ligand,[12c] the amount of base can
be reduced to only 10 mol% in our catalytic system. Further-
more, increasing the temperature from 08C to room tempera-
[a] L. Dai, D. Xu, L.-W. Tang, Prof. Dr. Z.-M. Zhou
R&D Centre of Pharmaceuticals
School of Chemical Engineering and the Environment
Beijing Institute of Technology
5th Zhongguancun South Street, Haidian District, Beijing (P.R. China)
E-mail: zzm@bit.edu.cn
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201403048.
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Table 1. Screening of asymmetric 1,3-dipolarcycloaddition of imino ester
2a and alkylidene malonate 3a.
Table 2. Substrate scope of CuII-catalyzed asymmetric 1,3-dipolar cyclo-
addition of imino ester 2a and various alkylidene malonates 3.[a]
Entry
R2
Product
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
p-MeC6H4
p-FC6H4
4ab
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
98
99
98
98
96
98
99
95
94
98
77
94
88
97.4
98.2
98.8
97.4
96.0
95.2
98.0
97.2
92.0
97.6
81.2
92.6
98.0
p-ClC6H4
o-ClC6H4
m-ClC6H4
p-BrC6H4
o-BrC6H4
m-BrC6H4
p-NO2C6H4
1-naphthyl
2-furyl
9
10
11
12
13
4am
4an
4ao
Entry [M]
Ligand[a] S/C Solvent Base
Yield ee
[%][b] [%][c]
2-thienyl
cyclohexyl
1
2
3
4
5
6
7
8
CuClO4
1a
1b
1c
1d
1e
1 f
1g
1h
1i
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
25 CH2Cl2
50 CH2Cl2
100 CH2Cl2
25 THF
25 Et2O
25 PhMe
25 acetone Cs2CO3 92
25 CH3CN
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
Cs2CO3 98
45.6
–
–
–
–
[a] All of the reactions were carried out with 0.25 mmol of 2a and
0.275 mmol of 3 in 5 mL CH2Cl2. [b] Isolated yields. [c] Determined by
chiral HPLC.
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
AgOAc
Cu(OTf)2
CuCl2·2H2O
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cu(OAc)2·H2O 1h
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
–
–
–
Cs2CO3 96
Cs2CO3 84
Cs2CO3 99
Cs2CO3 87
Cs2CO3 99
Cs2CO3 99
95.6
53.4
96.2
75.0
81.2
97.8
–
99.0
99.0
96.0
95.4
94.0
97.0
91.8
98.6
99.0
–
shown in Table 2, excellent yields and enantioselectivities
(92.0–98.8% ee) of pyrrolidines 4ab–4aj were obtained
(Table 2, entries 1–8). The position and electronic properties of
the substituents on the aromatic rings exhibited a limited
impact on the reaction. Both ortho- and meta-substituted aryli-
dene malonates underwent the 1,3-dipolar cycloaddition, af-
fording quantitative yields and 96.0–97.8% ee (Table 2, en-
tries 4, 5, 7, and 8). Notably, when an arylidene malonate bear-
ing a strong electron-withdrawing nitro group was used as the
substrate, the enantioselectivity of 4ak decreased to 92.0% ee
(Table 2, entry 9).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1h
1h
1h
Cs2CO3
–
Cs2CO3 99
Cs2CO3 99
Cs2CO3 98
Cs2CO3 57
Cs2CO3 92
Cs2CO3 99
Cs2CO3 99
Cs2CO3 93
The arylidene malonate formed from 1-naphthylaldehyde
also worked well in this transformation, producing the corre-
sponding 4al in 97.6% ee (Table 2, entry 10). The arylidene
malonate bearing a thienyl moiety was also tolerated in this re-
action, and the cycloadduct was obtained in 94% yield and
92.6% ee, even though the sulfur atom was potentially coordi-
nated to the Cu salt (Table 2, entry 12). Moreover, cyclohexyli-
dene malonate was also investigated, and product 4ao was
obtained in 88% yield and 99.0% ee without any increase in
the catalyst loading (Table 2, entry 13).
KOAc
CsOAc
DIPEA
K2CO3
–
–
99
98
–
95.4
99.2
92.6
26[d,e] Cu(OAc)2·H2O 1h
Cs2CO3 99
[a] Structures of the ligands are shown above; TBS=tert-butyldimethylsil-
yl; TMS=trimethylsilyl. [b] Isolated yields. [c] Determined by chiral HPLC.
[d] Reacted at room temperature. [e] Reacted in 2 h. S/C=substrate/cata-
lyst ratio
ture accelerated the reaction, but decreased the enantioselec-
tivity of the pyrrolidine product (Table 1, entry 26).
The reaction proceeded smoothly even on a 5 mmol scale
under the same reaction conditions. Treatment of 0.885 g of
2a and 1.79 g of 3i afforded product 4ai in 95% yield and
99.2% ee. The absolute configuration of 4ai was determined
by using X-ray diffraction (Figure 1, CCDC-1038320), and was
revealed to be exo-(2R, 3R, 5R).
Based on the above results, the optimized conditions for the
asymmetric 1,3-dipolar cycloaddition were as follows: 4 mol%
Cu(OAc)2·H2O/1h catalyst, CH2Cl2 as the solvent, and 10 mol%
K2CO3 as the base at 08C. We next examined the scope of the
reaction with arylidene malonate substrates under the opti-
mized reaction conditions. An array of arylidene malonates, 3,
derived from aldehydes with electron-donating and electron-
withdrawing substituents were tested with imino ester 2a. As
With imino esters, a substituent effect was observed. Specifi-
cally, the position of the substituent and the electronic nature
of the substrate affected the yields and enantioselectivities of
the product. As shown in Table 3, the reaction between 3a
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Table 4. CuII-catalyzed asymmetric 1,3-dipolar cycloaddition of imino
esters 2a and different dipolarophiles.[a]
Entry
Product
Yield
[%]
ee
[%]
1
2
90
95
95.2
63.0
3[b]
98
99
87.0
99.0
4[c]
Figure 1. X-ray structure of 4ai (CCDC-1038320).
[a] All of the reactions were carried out with 0.25 mmol of 2a and
0.275 mmol of the dipolarophiles in 5 mL CH2Cl2 with 4 mol% catalyst at
08C. Isolated yields; ee was determined by chiral HPLC. [b] DIPEA was
used as the base. [c] exo/endo was >98:2 as determined by H NMR spec-
troscopy.
Table 3. Substrate scope of CuII-catalyzed asymmetric 1,3-dipolar cyclo-
addition of various imino esters 2 and alkylidene malonate 3a.[a]
1
In addition, different types of dipolarophiles were employed
in this 1,3-dipolar cycloaddition. The results are listed in
Table 4. By changing the ester moiety of the alkylidene from
an ethyl to a methyl group, the enantioselectivity of the corre-
sponding adduct decreased slightly to 95.2%. When malononi-
trile benzylidene was utilized, the enantioselectivity was only
63.0%. Fortunately, the nitroalkene was a viable dipolarophile
under the optimized conditions, and resulted in the corre-
sponding adduct in 99% yield and 99.0% ee.
Entry
R1
Product
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
p-MeC6H4
p-MeOC6H4
p-FC6H4
4ba
4ca
4da
4ea
4 fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4na
98
82
97
98
94
88
96
98
85
98
96
77
96
96.0
94.8
96.2
96.8
87.0
85.2
95.8
90.4
82.0
85.2
90.0
78.0
87.4
p-ClC6H4
o-ClC6H4
m-ClC6H4
p-BrC6H4
o-BrC6H4
m-BrC6H4
p-NO2C6H4
1-naphthyl
2-furyl
Based on the configuration of the product, the enantioselec-
tivity could be rationalized by using proposed transition
state I, as shown in Figure 2. The azomethine ylide, generated
9
10
11
12
13
2-thienyl
[a] For reaction conditions see Table 2. [b] Isolated yields. [c] Determined
by chiral HPLC.
and para-substituted imino esters afforded excellent yields and
high enantioselectivities (Table 3, entries 1–4). However, the
imino esters bearing ortho- or meta-substituted groups on the
aromatic ring only afforded 82.0–87.0% ee (Table 3, entries 5, 6,
8, and 9). Furthermore, the imino ester with an electron-with-
drawing nitro group afforded cycloadduct 4ka with only
85.2% ee (Table 3, entry 10). The 1-naphthyl derivative of the
imino ester afforded the corresponding product 4la in 96%
yield and 90.0% ee (Table 3, entry 11). Heteroaryl imino esters
could also be used as substrates. However, the cycloadducts
were only obtained in moderate enantioselectivities (Table 3,
entries 12 and 13).
Figure 2. Proposed transition state leading to the exo product.
from the imino ester, coordinates to the CuII catalyst in a dis-
torted tetrahedral geometry. The cycloaddition favors the exo
product, possibly because of the steric repulsion between the
phenyl rings adjacent to the phosphorus atom and the aro-
matic ring of alkylidene malonates. Furthermore, the Si face of
the azomethine ylide is shielded by the substituent on the oxa-
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In conclusion, the newly synthesized siloxane-substituted
FOXAP ligand was successfully applied in the enantioselective
1,3-dipolar cycloaddition of azomethine ylides with alkylidene
malonates. The cycloaddition proceeded by using 4 mol% CuII
catalyst loading and 10 mol% base. The polysubstituted pyrro-
lidine derivatives were obtained in good yields (77–98%) and
excellent enantioselectivities (up to 99.2% ee). Aliphatic-substi-
tuted products could also be obtained without increasing the
catalyst loading. Studies regarding further applications of the
novel siloxane-substituted FOXAP ligands in other catalytic re-
actions are currently underway.
Acknowledgements
We thank the National Natural Science Foundation of China for
financial support (Grant No. KZ200610011006).
Keywords: asymmetric catalysis · cycloaddition · ferrocene ·
malonates · ylides
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Received: December 22, 2014
Published online on && &&, 0000
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COMMUNICATIONS
L. Dai, D. Xu, L.-W. Tang, Z.-M. Zhou*
&& – &&
A CuII-N,P Oxazolinylferrocene Ligand
Complex for the Asymmetric [3+2]
1,3-Dipolar Cycloaddition of
Azomethine Ylide with Malonates
Dipolar cycloaddition: A series of enan-
tioselective pyrrolidine-2,4,4-tricarboxy-
late derivatives were synthesized by the
[3+2] 1,3-dipolar cycloaddition of azo-
methine ylide with alkylidene malo-
nates. By using 4 mol% of a CuIIÀN,P ox-
azolinylferrocene ligand complex and 10
mol% of a base, pyrrolidine analogues
were obtained in high yields (77–99%)
and excellent enantioselectivities (up to
99% ee).
&
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
6
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!