Organocatalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadienes and aldehydes

Article abstract of DOI:10.1002/anie.200804183

(Chemical Equation Presented) Water is crucial for high transformation efficiency in the title reaction catalyzed by the α,α- diphenylprolinol derivative 1. Excellent stereoselectivities were observed for a broad spectrum of substrates (see scheme; TMS = trimethylsilyl, Tos = p-toluenesulfonyl). A diverse range of chiral piperidine derivatives and other valuable compounds can be prepared from the hemiaminal products.

Full text of DOI:10.1002/anie.200804183

Angewandte
Chemie
DOI: 10.1002/anie.200804183
Asymmetric Catalysis
Organocatalytic Asymmetric Inverse-Electron-Demand Aza-Diels–
Alder Reaction of N-Sulfonyl-1-aza-1,3-butadienes and Aldehydes
Bo Han, Jun-Long Li, Chao Ma, Shan-Jun Zhang, and Ying-Chun Chen*
The development of efficient procedures to access optically
pure piperidines has provoked continuing interest, as such
compounds have been used widely in the construction of
natural products and pharmaceutical compounds.[1] The
stereoselective aza-Diels–Alder reaction (ADAR) is one of
the most convergent strategies for the synthesis of chiral
piperidine derivatives. As a complementary alterative to the
well-established formal cycloaddition of dienes and imines
catalyzed by metal complexes or organic molecules,[2,3] Boger
and co-workers introduced inverse-electron-demand aza-
Diels–Alder reactions of N-sulfonyl-1-aza-1,3-butadienes
and electron-rich alkenes.[4] These reactions generally exhib-
ited high regiospecificity and diastereoselectivity with the
characteristics of a concerted [4+2] cycloaddition mechanism.
Although the utility of these reactions has been explored
fruitfully over the past two decades, quite limited progress has
been made in catalytic asymmetric variants.[5] Recently, Bode
and co-workers developed an asymmetric ADAR of
N-sulfonyl a,b-unsaturated aldimines and b-activated enals
with a chiral N-heterocarbene catalyst,[6] and later Carretero
and co-workers reported a Lewis acid catalyzed ADAR of
N-(heteroaryl)sulfonyl a,b-unsaturated ketimines with vinyl
ethers.[7]
ambient temperature after 72 h (Table 1, entry 1). Subse-
quently, it was found that the adduct 5 was formed as a rather
stable compound in the reaction.[8a] Similar phenomena were
observed in THF or MeOH (Table 1, entries 2 and 3). The
conversion was improved in acetonitrile: The expected hemi-
aminal 4a was formed with excellent stereoselectivity and
isolated as a fairly stable compound in moderate yield
(Table 1, entry 4; d.r. > 99:1, 96% ee). Moreover, we found
that the addition of water led to a dramatic acceleration of the
reaction (Table 1, entry 5); better results were observed when
a 10:1 mixture of CH3CN and H2O was used (Table 1,
entry 6).[11] Apparently, water is helpful for the hydrolysis of
intermediate 5 to release the catalyst 1a and thus enable
catalytic turnover. The acid additive has a great effect on the
reaction; almost no reaction occurred when the stronger
p-toluenesulfonic acid (p-TSA) was used in place of benzoic
acid (Table 1, entry 7). The enantioselectivity could be
Table 1: Optimization of the organocatalytic ADAR of the N-tosyl-1-aza-
1,3-butadiene 2a and butyraldehyde (3a).[a]
In 2003, Juhl and Jørgensen reported an inverse-electron-
demand hetero-Diels–Alder reaction of aldehydes and b,g-
unsaturated a-ketoesters catalyzed by a chiral secondary
amine.[8a] The chiral enamine generated in situ as an electron-
rich alkene is crucial for the success of the reaction.[8]
Encouraged by these elegant achievements, we envisaged
that an unprecedented asymmetric ADAR of N-sulfonyl-1-
aza-1,3-butadienes and aldehydes might be developed by
employing a similar strategy.
We initially investigated the reaction of the N-tosyl imine
of chalcone, 2a, with butyraldehyde (3a) in the presence of
the readily available a,a-diphenylprolinol trimethylsilyl ether
1a (10 mol%) and benzoic acid (10 mol%) in toluene.[9,10]
The ADAR product 4a was obtained in less than 10% yield at
Entry
1
Acid
Solvent
Yield [%][b]
ee [%][c]
1[d]
2[d]
3[d]
4[d]
5[f]
6
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
BzOH
BzOH
BzOH
BzOH
BzOH
BzOH
p-TSA
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
toluene
THF
MeOH
MeCN
<10
<10
<10
66
69
89
<10
88
88
63
86
n.d.[e]
n.d.
n.d.
96
92
95
n.d.
97
95
96
92
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeOH/H2O
THF/H2O
dioxane/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
7
8
9[d]
10[d]
11
12
13
14
[*] B. Han, J.-L. Li, C. Ma, S.-J. Zhang, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug Targeting and Drug-Delivery Systems of the
Ministry of Education, Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
60
49
<10
94
95
n.d.
Fax : (+86)28 85502609
E-mail: ycchenhuaxi@yahoo.com.cn
[a] Reaction conditions (unless otherwise noted): 2a (0.1 mmol), 3a
(0.2 mmol), 1 (0.01 mmol), acid (0.01 mmol), organic solvent/H2O
(1.1 mL, 10:1), room temperature, 24 h. [b] Yield of the isolated product.
[c] The ee value was determined by HPLC on a chiral phase; d.r.>99:1.
[d] Reaction time: 72 h. [e] Not determined. [f] The reaction was carried
out in CH3CN/H2O (5:1). Bz=benzoyl, TBS=tert-butyldimethylsilyl,
TES=triethylsilyl, TMS=trimethylsilyl.
Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy
West China Hospital, Sichuan University
Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804183.
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improved slightly by adding acetic acid (Table 1, entry 8).
Inferior results were obtained with other organic solvent/H2O
mixtures (Table 1, entries 9–11). The bulkier silyl ethers 1b
and 1c gave similar enantioselectivity but with lower catalytic
activity (Table 1, entries 12 and 13); the secondary amine 1d
with strong electron-withdrawing substituents on the aryl
rings failed to catalyze the model reaction (Table 1, entry 14).
Having established optimal reaction conditions, we
explored the scope of this ADAR. Thus, N-sulfonyl-1-aza-
1,3-butadienes 2 were treated with aldehydes 3 in the
presence of 1a (10 mol%) and AcOH (10 mol%) in a
mixture of CH3CN and H2O (10:1) at room temperature.
Hemiaminals 4 with excellent diastereomeric ratios (d.r. >
99:1) were isolated directly and were stable enough for
analysis by various methods. For the reactions with butyr-
aldehyde, a wide range of substituents could be present at the
b position of the N-tosyl a,b-unsaturated ketimine 2. A
variety of aryl or heteroaryl groups at this position of the
Figure 1. X-ray crystal structure of the enantiomerically pure hemiami-
nal 4l.
a,b-unsaturated ketimine with a b-alkyl group (Table 2,
entry 9). A b-activated ketimine, with an ester substituent in
the b position, exhibited higher reactivity, and excellent
enantioselectivity was also observed (Table 2, entry 10).
=
C C bond had a limited effect on the enantioselectivity of the
reaction, and excellent ee values were observed (Table 2,
=
entries 1–8). Good results were also attained with an
The substituent on the C N bond was also varied.
Outstanding enantioselectivities were observed for substrates
with electron-donating or electron-withdrawing aryl groups at
this position (Table 2, entries 11–15). The ketimine derived
from dibenzylideneacetone was a good substrate, and thus
another functionality could be introduced into the product
(Table 2, entry 16). However, an alkyl-substituted ketimine
showed no reactivity toward butyraldehyde (Table 2,
entry 17), and an a,b-unsaturated aldimine underwent
decomposition (Table 2, entry 18).
Table 2: Asymmetric ADAR of N-tosyl-1-aza-1,3-butadienes 2 and alde-
hydes 3.[a]
Entry
R
R1
R2
4
Yield[b] ee[c]
[%]
[%]
Other linear aliphatic aldehydes could be applied
smoothly as substrates in the ADAR reaction (Table 2,
entries 19 and 20); however, the attempted reaction of
branched isovaleraldehyde with 1-aza-1,3-butadiene 2a
failed, probably because of steric reasons (Table 2,
entry 21). The use of aqueous acetaldehyde was also unsuc-
cessful under the current catalytic conditions (Table 2,
entry 22).[13] When this catalytic ADAR was conducted on a
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-ClC6H4
m-ClC6H4
Et
Et
Et
4a
4b
4c
4d
4e
4 f
4g
4h
4i
88
85
92
81
78
40
83
87
83
95
85
82
97
98
99
95
96
99
98
98
93
99
99
98[g]
99
99
94
99
–
m-MeOC6H4 Et
p-MeC6H4
1-Np
2-furyl
2-thienyl
Me
COOEt
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
6[d]
7[e]
8[e]
9
Ph
Ph
10[f]
11
12
13
14
15[e]
16[d]
17
18
19
20[d]
21
22
23[h]
4j
4k
4l
p-MeC6H4
p-ClC6H4
o-ClC6H4
m-BrC6H4
1-Np
=
Ph
Ph
Ph
4m 74
4n
4o
4p
–
–
4q
86
83
91
–
PhCH CH Ph
Me
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
–
–
Ph
Ph
Ph
Ph
Ph
92
72
–
–
82
98
99
–
–
96
BnO(CH2)2 4r
iPr
H
–
–
4a
Et
[a] Reaction conditions (unless otherwise noted): 2 (0.1 mmol), 3
(0.2 mmol), 1a (10 mol%), AcOH (10 mol%), CH3CN/H2O (1.1 mL,
10:1), room temperature, 24 h. [b] Yield of the isolated product. [c] The
ee value was determined by HPLC on a chiral phase; d.r.>99:1.
[d] Reaction time: 72 h. [e] Reaction time: 48 h. [f] Reaction time: 12 h.
[g] The absolute configuration of 4l was determined by X-ray crystal-
structure analysis (Figure 1).[12] The absolute configuration of the other
products was assigned by analogy. [h] The reaction was carried out on a
1.0 mmol scale with a reaction time of 48 h. Bn=benzyl, Np=naphthyl.
Scheme 1. Synthetic transformations of the chiral hemiaminal 4a:
a) PCC, 408C, 6 h; b) Et3SiH, BF3·Et2O, À788C, 4 h; c) Et3SiH,
BF3·Et2O, room temperature, 12 h; d) FeCl3·6H2O, CH2Cl2, 08C, 8 h;
e) MnO2, CHCl3, room temperature, 12 h. PCC=pyridinium chloro-
chromate.
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Chem. Soc. 2007, 129, 10336; e) Y. Hayashi, H. Gotoh, R. Masui,
H. Ishikawa, Angew. Chem. 2008, 120, 4076; Angew. Chem. Int.
Ed. 2008, 47, 4012.
larger scale, similar good results were observed (Table 2,
entry 23).
The chiral hemiaminal 4a could be converted smoothly
into a number of valuable compounds (Scheme 1). Upon
oxidation with PCC (pyridinium chlorochromate), lactam 6
was produced without any racemization. The hydroxy group
of 4a was removed chemoselectively to give tetrahydropyr-
idine 7 by reduction with Et3SiH/BF3·Et2O at À788C, whereas
the enamide functionality was also reduced to afford piper-
idine 8 with excellent diastereoselectivity when the 4a was
treated with these reagents at ambient temperature. Hemi-
aminal 4a could also be hydrolyzed to the enantiomerically
enriched anti 1,5-dicarbonyl compound 9. Since no direct
asymmetric intermolecular Michael addition of aliphatic
aldehydes to chalcones has been developed,[14] this method
might serve as an alternative approach to this type of chiral
building block. Finally, hemiaminal 4a was oxidized effi-
ciently to the trisubstituted pyridine 10.
[4] a) D. L. Boger, A. M. Kasper, J. Am. Chem. Soc. 1989, 111, 1517;
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[5] For selected examples of diastereoselective ADARs of 1-
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In conclusion, we have presented a highly stereoselective
inverse-electron-demand aza-Diels–Alder reaction of N-sul-
fonyl-1-aza-1,3-butadienes and aldehydes that proceeds
under aminocatalysis with a chiral secondary amine. Excel-
lent enantioselectivities (up to 99% ee) were observed for a
broad spectrum of substrates under mild conditions. More-
over, a variety of chiral piperidine derivatives and other
useful compounds could be prepared readily from the hemi-
aminal adducts. We are currently investigating the catalytic
mechanism of the reaction[14] and the development of new
asymmetric reactions catalyzed by chiral amines.
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Received: August 25, 2008
Published online: October 20, 2008
Keywords: aldehydes · aminocatalysis · asymmetric catalysis ·
.
aza-Diels–Alder reaction · piperidines
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[15] As suggested by Juhl and Jørgensen for a related system,[8a] the
catalyst may induce the ketimine to approach the aldehyde in an
endo-selective manner to afford the observed chiral hemiaminal
4. However, at present a formal Michael addition followed by a
ring-closure process cannot be ruled out (see reference [8c]).
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Angew. Chem. Int. Ed. 2008, 47, 9971 –9974