Direct asymmetric aza Diels-Alder reaction catalyzed by chiral 2-pyrrolidinecarboxylic acid ionic liquid

Article abstract of DOI:10.1016/j.catcom.2009.12.021

The utility of [EMIm][Pro] as an efficient catalyst for the one-pot direct asymmetric aza Diels-Alder reaction has been developed. A set of cyclic α,β-unsaturated ketones have been explored in up to 93% yield with up to >99/1 dr and >99% ee. Moreover, the catalytic system can be recycled and reused for six times without any significant loss of catalytic activity.

Full text of DOI:10.1016/j.catcom.2009.12.021

Catalysis Communications 11 (2010) 567–570
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Direct asymmetric aza Diels–Alder reaction catalyzed by chiral
2-pyrrolidinecarboxylic acid ionic liquid
*
Xin Zheng, Yunbo Qian, Yongmei Wang
Department of Chemistry, The Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The utility of [EMIm][Pro] as an efficient catalyst for the one-pot direct asymmetric aza Diels–Alder reac-
Received 10 September 2009
Received in revised form 29 November 2009
Accepted 16 December 2009
Available online 23 December 2009
tion has been developed. A set of cyclic a,b-unsaturated ketones have been explored in up to 93% yield
with up to >99/1 dr and >99% ee. Moreover, the catalytic system can be recycled and reused for six times
without any significant loss of catalytic activity.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Ionic liquid
Aza Diels–Alder reaction
Asymmetric
1. Introduction
organocatalysts [31,32] and an increasing number of reactions cat-
alyzed by ionic liquids, we proposed the combination of proline as
The synthesis of enantiomerically enriched nitrogen-containing
heterocylic compounds is of significantly important in organic syn-
thesis and in the chemical industry. The asymmetric aza Diels–Al-
der reaction has emerged as a valuable synthetic methodology to
construct six-membered nitrogen-containing rings for complex
molecules such as alkaloids, azasugars and piperidine derivatives
[1,2]. Over the past decades, Lewis acids [3–5], Brønsted acids
[6,7] and rare metal salts [8,9] have been investigated as the cata-
lysts for aza Diels–Alder reaction. Only a few examples have been
reported concerning the direct asymmetric aza Diels–Alder reac-
tion catalyzed by organocatalysts [10,11].
In recent years, a growing number of chiral ionic liquids have
been considered as intensively promising green reaction media
[12–17], not only due to their favorable properties including reus-
ability, nonvolatile nature and high thermal stability but also due
to their unique selectivity and reactivity. Furthermore, ionic liquids
have currently been widely employed either as catalysts or sol-
vents for a vast majority of examples [12–20], especially the
Diels–Alder reactions [20–30]. Recently, Giang Vo-Thanh and
coworkers reported that a novel chiral ammonium and imidazoli-
um-based ionic liquid could catalyze the aza Diels–Alder reaction
[27–29]. However, there is no report that ionic liquid catalysts
accompanying chiral anion as a stereocontrolling moiety for the di-
rect asymmetric aza Diels–Alder reaction. In view of a myriad of
examples employing proline and its derivatives as the successful
an effective anion module with ionic liquids in promoting enantio-
selective aza Diels–Alder reaction. Previously, we have reported
that [EMIm][Pro] (1) ionic liquid using (S)-proline as anion (1-
ethyl-3-methylimidazolium-(S)-2-pyrrolidinecarboxylic acid salt)
could facilitate the asymmetric Michael addition reaction via en-
amine mechanism [33]. This chiral ionic liquid is readily available
from simple and inexpensive starting materials and we routinely
prepare it on large scale.
In light of these facts, here we report the application of
[EMIm][Pro] (1) as an effective catalyst for the direct asymmetric
aza Diels–Alder reaction. This direct asymmetric aza Diels–Alder
reaction induced by the chiral anion ionic liquid that may greatly
enlarge the extension of design and application of chiral ionic liq-
uids in organic synthesis.
2. Experimental
2.1. General
1H and 13C NMR spectra were measured on either a Bruker-DPX
400 or AV-400 spectrometer with tetramethylsilane (TMS) as the
internal standard. HPLC analysis was performed on Shimadzu
CTO-10AS by using a Chiralpak AD-H or OD-H column purchased
from Daicel Chemical Industries. All yields refer to isolated prod-
ucts after purification. All chemicals (AR grade), unless otherwise
stated, were commercially available and used without further
purification.
* Corresponding author. Tel./fax: +86 22 23502654.
E-mail address: ymw@nankai.edu.cn (Y. Wang).
1566-7367/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2009.12.021

568
X. Zheng et al. / Catalysis Communications 11 (2010) 567–570
Table 1
2.2. Preparation of amino acid ionic liquid [EMIm][Pro] 1
Solvent screen for the direct asymmetric aza Diels–Alder reaction.a
[EMIm][Pro] could be easily synthesized from commercially
available chemicals in 80% overall yield according to the reference
(Scheme 1) [34]. 1H NMR (300 MHz, DMSO-d6) d (ppm): 9.67 (s,
1H), 7.87 (s, 1H), 7.79 (s, 1H), 4.25 (q, J = 10.17 Hz, 2H), 3.90 (s,
3H), 3.32 (broad, 1H), 2.97–3.05 (m, 1H), 2.72 (broad, 1H), 1.83–
1.90 (m, 1H), 1.69–1.74 (m, 1H), 1.53–1.59 (m, 2H), 1.42 (t,
J = 7.30, 7.30 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) d (ppm):
176.0, 136.9, 123.5, 121.9, 61.8, 46.4, 44.0, 35.5, 30.6, 25.3, 15.1.
ESI-MS: m/z C6H11Nþ (M+) Calc. 111.09. Found: 111.21; C5H8NOꢀ
c
Entry
Solvent
Yieldb (%)
dr (endo/exo)
ee (%)d
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
DMSO
THF
NMP
Dixone
DMF
[BMIm][BF4]
CHCl3
ClCH2CH2Cl
Toluene
MeOH
67
45
57
47
58
40
60
56
54
51
52
30
46
70/30
51/49
67/33
55/45
57/43
68/32
52/48
56/43
66/34
53/47
62/38
55/45
61/39
94
51
78
53
85
42
68
63
74
11
24
24
51
2
2
(Mꢀ), Calc. 114.06, Found: 114.21. ½a 2D5
ꢁ
= +51.0 (c1, MeOH).
2.3. Typical procedure for one-pot asymmetric Diels–Alder reaction
A 25 mL round-bottomed flask was charged with p-anisidine
(0.3 mmol), aqueous formaldehyde (0.1 mmol, 36 vol.% aqueous
solution), 1 (30 mol%) and CH2Cl2 (0.5 mL). After being stirred vig-
orously at room temperature until the imine was formed as mon-
itored by TLC, 2-cyclohexen-1-one (0.5 mmol) was added to the
mixture. When the reaction was finished, the reaction mixture
was worked up by addition of saturated ammonium chloride,
and extracted with AcOEt. The organic layers were washed with
water, dried over Na2SO4, filtered, concentrated under vacuum
and purified by flash column chromatography to afford the desired
aza Diels–Alder product.
9
10
11
12
13
t-BuOH
a
The reaction was performed using 2-cyclohexen-1-one (0.5 mmol), aqueous
formaldehyde (0.1 mmol, 36 vol.% aqueous solution), p-anisidine (0.2 mmol) and
catalyst (30 mol%) in a solvent (0.5 mL) for 15 h.
b
Yield of product isolated by column chromatography.
Determined by 1H NMR analysis.
c
d
The ee of the endo isomer was determined by chiral-phase HPLC using a Daicel
Chiralpak OD-H column.
2.4. Reusability of the catalyst
Table 2
A catalytic amount of 1 (30 mol%) was added to a solution of p-
anisidine (0.3 mmol), aqueous formaldehyde (0.1 mmol, 36 vol.%
aqueous solution) at room temperature. The progress of the reac-
tions was monitored by TLC. After the imine was formed, Ketone
2b was added to the mixture. In the end, the reaction was recov-
ered directly for the next cycle after full extraction of the product
three times with 5 mL ethyl ether per extraction and drying in
vacuo.
Optimization of the effect of the ratio of reactants for the direct asymmetric aza
Diels–Alder reaction.
Entry
2a/3/4a
Yielda (%)
dr (endo/exo)b
ee (%)c
1
2
3
4
5
6
5:1:2
5:1:2.5
5:1:3
2:1:3
3:1:3
4:1:3
6:1:3
5:1:3
5:1:3
67
68
75
40
48
50
48
70
66
70/30
71/29
84/16
68/32
68/32
81/19
82/18
66/34
58/42
94
91
98
62
63
81
76
52
28
7
3. Results and discussion
8d
9e
The initial investigation was carried out among 2-cyclohexen-1-
one (2a), aqueous formaldehyde (3) and p-anisidine (4a) in DMSO
at room temperature in the presence of 30 mol% 1. To our delight,
the reaction proceeded readily, favoring the endo product 5a with
78% ee and 67/33 dr (Table 1, entry 3). In order to increase the yield
and enantiomeric excess, we screened a variety of solvents. When
the reaction was conducted in CH2Cl2, the desired product 5a was
isolated in higher yield (67%) with 94% ee and 70/30 dr than its
counterparts (Table 1, entry 1).
To optimize the reaction condition, the proportion of reactants
was examined. When the ratio of 2a/3/4 was 5:1:3, the highest
yield (75%) were obtained (Table 2, entry 3). This constitutes a sig-
nificant improvement of yields as compared to proline-catalyzed
a
b
c
Yield of product isolated by column chromatography.
Determined by 1H NMR analysis.
The ee of the endo isomer was determined by chiral-phase HPLC using a Daicel
Chiralpak OD-H column.
d
20% catalyst.
10% catalyst.
e
direct aza Diels–Alder reaction [10] (30% yield). Lowering the cat-
alyst loading to 20 mol% and 10 mol% respectively resulted in shar-
ply decreasing dr and ee values (Table 2, entries 8–9).
Having achieved the optimized reaction conditions, we ex-
tended the scope of [EMIm][Pro] catalyzed direct asymmetric aza
Diels–Alder reaction on a series of olefine ketones and the results
are summarized in Table 3. In most cases, the reactions proceeded
efficiently to provide exclusively the endo products 5 in modest to
good yields (40–93%) with high enantioselectivities (92–>99%) and
diastereoselectivities range from 84/16 to >99/1. However, only
trace amounts of the corresponding product 5l was observed in
the reaction (Table 3, entry 12). It should be noted that the aza
Diels–Alder reactions with aniline and anilines bearing an
electron-donating substituent at the para position formed the
endo-isomers in higher yields in comparison to the halogenated
anilines. Surprisingly, when the direct enantioselective aza Diels–
Alder reaction was treated with preformed imines under the same
Scheme 1. Conditions: (a) CH3CH2Br, CH3CO2C2H5, 4, 80%; (b) 201 ꢂ 7 styrene-
DVB; (c) proline, 80%.

X. Zheng et al. / Catalysis Communications 11 (2010) 567–570
569
Table 3
One-pot asymmetric aza Diels–Alder reactions catalyzed by [EMIm][Pro].a
Table 4
Recycling of the catalytic system for asymmetric Diels–Alder reaction.a
Entry Ketone
1
Ar
Product
Yieldb dr (endo/ ee
(%)
exo)c
(%)d
Run
Yield (%)b
dr (endo/exo)c
ee (%)d
PMP
75
84/16
98
1
2
3
4
5
6
72
71
71
70
71
70
>99/1
>99/1
>99/1
99/1
98/2
98/2
>99
>99
>99
98
97
95
2
3
4
5
6
Ph
65
51
40
57
72
94/6
96
99
94
98
>99
a
The reaction was performed using ketone 2b (0.5 mmol), aqueous formalde-
hyde (0.1 mmol, 36 vol.% aqueous solution), p-anisidine (0.3 mmol) and catalyst
(30 mol%) in CH2Cl2 (0.5 mL) for 15 h.
4-
FC6H4
>99/1
>99/1
>99/1
>99/1
b
Yield of product isolated by column chromatography.
Determined by 1H NMR analysis and HPLC.
c
d
4-
BrC6H4
The ee of the endo isomer was determined by chiral-phase HPLC using a Daicel
Chiralpak OD-H column.
4-
ClC6H4
The absolute configurations of the aza Diels–Alder products
have been determined by chiral-phase HPLC analysis and by com-
parison with the literature [10]. Next, we continued to explore the
recyclability of 1 which is important from the viewpoint of envi-
ronment friendly and cost-effectiveness. We carried out the model
study by using ketone 2b and p-anisidine in the presence of
30 mol% 1 (Table 4). After the reaction was completed, the mixture
was easily extracted to afford the adduct, avoiding the need to re-
course to stringent anhydrous conditions. It can be reused for six
successive cycles with comparable enantioselectivities and yields
without significant loss of catalytic activity.
PMP
Ph
7
8
9
89
58
90
>99/1
>99/1
>99/1
98
99
92
4-
FC6H4
4. Conclusion
In summary, we have demonstrated the first direct asymmetric
aza Diels–Alder reaction catalyzed by [EMIm][Pro] 1 ionic liquid.
The method has proved to be practical and convenient, furnishing
the resulting products in modest to good yields with excellent
enantioselectivities and diastereomeric ratios. Additionally, this
catalyst is easily prepared from rather inexpensive starting materi-
als. The catalyst can be recovered and reused up to six times
through a simple extraction protocol. Further research and applica-
tion of this catalyst to other reactions is underway.
4-
ClC6H4
10
11
12
PMP
Ph
85
99/1
98:2
n.d.
98
93
99
Acknowledgments
PMP
<5%
n.d.
The work was financially supported by 973 Project (no.
2010CB833300, China). We also thank the Nankai University State
Key Laboratory of Elemento-Organic Chemistry for support.
a
b
c
Conditions: see typical procedure.
Yield of product isolated by column chromatography.
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d
The ee of the endo isomer was determined by chiral-phase HPLC using a Daicel
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