Aminocatalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of N-Ts-1-aza-1,3-butadienes based on coumarin cores

Article abstract of DOI:10.1039/b925424b

The asymmetric inverse-electron-demand aza-Diels-Alder reaction of N-Ts-1-aza-1,3-butadienes derived from 3-argiocarbonylcoumarins and acetaldehyde has been developed using chiral secondary aminocatalysis, giving tricyclic chroman-2-one derivatives in hig

Full text of DOI:10.1039/b925424b

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Aminocatalytic asymmetric inverse-electron-demand aza-Diels–Alder
reaction of N-Ts-1-aza-1,3-butadienes based on coumarin coresw
Jun-Long Li,a Si-Li Zhou,a Bo Han,a Li Wua and Ying-Chun Chen*ab
Received (in Cambridge, UK) 2nd December 2009, Accepted 25th January 2010
First published as an Advance Article on the web 11th February 2010
DOI: 10.1039/b925424b
The asymmetric inverse-electron-demand aza-Diels–Alder reaction
of N-Ts-1-aza-1,3-butadienes derived from 3-argiocarbonyl-
coumarins and acetaldehyde has been developed using chiral
secondary aminocatalysis, giving tricyclic chroman-2-one
derivatives in high enantioselectivities (up to 95% ee).
Coumarin, first isolated from tonka beans in 1820, represents
one of the most popular skeletons in the chemistry of natural
products.1 Over the past decades, numerous coumarin derivatives
and related compounds have been discovered or obtained
Scheme 1 Direct asymmetric reactions of acetaldehyde via enamine
synthetically, which exhibit broad biological activities as coronary
vasodilators,2 tautomerase inhibitors,3 anti-inflammatory
agents,4 selective FXIIa inhibitors,5 etc. Currently, their study
still remains an important topic in both organic chemistry and
pharmaceutical science.6
catalysis.
We initially investigated the possible cycloaddition reaction
of N-Ts-1-aza-1,3-butadiene 2a derived from 3-benzoylcoumarin
and aqueous acetaldehyde in 1,4-dioxane at room temperature
by the catalysis of readily available a,a-diphenylprolinol
O-TMS ether 1a (20 mol%) and benzoic acid (20 mol%).14
To our delight, this reaction proceeded smoothly, and the
desired hemiaminal 3a could be isolated easily, which was
better analysed as the dehydroxylated product 4a after reduction
with Et3SiH/BF3ÁEt2O.7 Unfortunately, the enantioselectivity
was quite disappointing (Table 1, entry 1). Poor conversion
was observed in acetonitrile owing to the low solubility of 2a,
and poor results were observed in THF (entries 2 and 3). We
found that a better ee value could be obtained at lower
temperature (entry 4), but a further improvement could not
be reached at À10 1C (entry 5). Subsequently, a number of
secondary amine catalysts were screened at room temperature.
Free prolinol 1b was almost inert (entry 6), and low ee values
were attained for catalysts 1c–1e, although good catalytic
activity was noted (entries 7–9). Gratifyingly, a bulky amine
1f, which was developed in our laboratory,15 delivered the
product with dramatically increased enantioselectivity without
affecting the reaction efficacy (entry 10). Finally, the product
4a was successfully obtained with an outstanding enantio-
selectivity and good yield at 5 1C for 24 h (entry 11).
Having established the optimal reaction conditions, we
studied the scope and limitations of the inverse-electron-
demand ARAR associated with acetaldehyde. As summarised
in Table 2, high enantioselectivities and good yields were
generally obtained for an array of N-Ts-1-aza-1,3-butadienes
bearing 2-aryl groups with diverse electron-withdrawing or
electron-donating substitutions (Table 2, entries 1–8). A
3-pyridyl-substituted azadiene could work efficiently, and
quite satisfying results were attained (entry 9). However, the
alkyl-substituted azadienes could not be synthesized and tested
due to their instability. On the other hand, azadienes with
electron-withdrawing or electron-donating substitutions on
Recently we have presented the highly enantioselective
inverse-electron-demand aza-Diels–Alder reaction (ADAR)
of N-sulfonyl-1-aza-1,3-butadienes bearing 2,4-disubstitutions
with aliphatic aldehydes7a or a,b-unsaturated aldehydes7b
through enamine or dienamine catalysis, respectively.
Later we recognised that N-sulfonyl-1-aza-1,3-butadienes
derived from 3-argiocarbonylcoumarins, which have
a
2,3,4-trisubstitution pattern, have also been investigated in
inverse-electron-demand ADAR by Boger and co-workers.8
However, to the best of our knowledge, such useful azadienes
have not been explored in a catalytic asymmetric variant yet.9
On the other hand, the simple acetaldehyde, also has not been
successfully utilised in direct cycloaddition reactions,10
probably due to a number of problems associated with
acetaldehyde via enamine activation:11 self-condensation,
oligomerisation and the challenge of stereocontrol, although
very recently some significant progress has been made in
the direct asymmetric aldol, Mannich or Michael addition
reactions.12 As a result of the biological relevance and the
urgent demand for new drug candidate frameworks, we were
encouraged to develop an asymmetric inverse-electron-
demand ADAR of N-Ts-1-aza-1,3-butadienes based on
coumarin skeletons and acetaldehyde, which could afford
optically active tricyclic chroman-2-one derivatives incorporating
a piperidine motif (Scheme 1).13
a Key Laboratory of Drug-Targeting and Drug Delivery System of
Education Ministry, Department of Medicinal Chemistry, West
China School of Pharmacy, Sichuan University, Chengdu 610041,
China. E-mail: ycchenhuaxi@yahoo.com.cn; Fax: +86 28 85502609
b State Key Laboratory of Biotherapy, West China Hospital,
Sichuan University, Chengdu, China
w Electronic supplementary information (ESI) available: Experimental
procedures and structural proofs. CCDC 756640 (4a). For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b925424b
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Table 1 Screening studies of the inverse-electron-demand ADAR of
azadiene 2a and acetaldehydea
Entry
Catalyst
Solvent
T
Yieldb (%)
eec (%)
1
2
3
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Dioxane
MeCN
THF
THF
THF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
rt
rt
rt
5 1C
79
o10
66
73
71
36
—
20
74
75
—
10
12
35
67
95
Fig. 1 X-ray structure of enantiopure 4a and proposed catalytic
mode in ADAR.
4d
5d
6
À10 1C
ADAR might be adopted,9c and the Si-face attack on
the azadiene 4a would afford the cyclic product 3a with
S-configuration at the benzylic carbon.
rt
o10
7
8
9
10
11d
rt
rt
rt
rt
65
84
80
82
79
Apart from acetaldehyde, we also tested the cycloaddition
reaction of propionaldehyde and azadiene 2a catalysed by 1a
(Scheme 2). The reaction proceeded efficiently, and piperidine
derivative 5 was isolated in excellent enantioselectivity and yield
after dehydroxylation. In contrast to the reported examples of
2,4-disubstituted 1-azadienes,7a in which only the trans-
isomers were obtained, compound 5 showed cis-configuration
contaminated by some minor trans-diastereomer.w
1f
5 1C
a
Unless noted otherwise, reaction was performed with azadiene 2a
(0.1 mmol), acetaldehyde (0.4 mmol), catalyst 1 (0.02 mmol), benzoic
acid (0.02 mmol) in solvent (1.0 mL) for 12 h. Then the hemiaminal 3a
b
was isolated and reduced to give compound 4a. Isolated yield for
c
two steps. Determined by chiral HPLC analysis. For 24 h.
d
On the other hand, we further investigated the reaction of
2,3,4-trisubstituted azadiene 2a with a,b-unsaturated aldehydes
catalysed by 1a via dienamine activation. As illustrated in
Scheme 3, for crotonaldehyde, similar b,g-regioselectivity was
observed to give aldehyde 6a in moderate enantioselectivity
and excellent diastereoselectivity compared with the ADAR of
2,4-disubstituted 1-azadienes.7b However, for penten-2-al,
complete b,g-regioselectivity was also attained in the adduct
6b, rather than the former a-regioselectivity in the cases of
2,4-disubstituted 1-azadienes.7b Thus, the different reaction
pathway might provide more synthetic potential for a,b-
unsaturated aldehydes via dienamine catalysis.w
Table 2 Asymmetric ADAR of azadienes 2 and acetaldehydea
Entry
R
Ar
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
79
91
82
81
79
84
86
87
75
89
86
95d
92
90
89
87
88
84
89
90
91
90
m-Br-C6H4
p-Cl-C6H4
p-F-C6H4
3,4-Cl2-C6H3
p-Me-C6H4
m-MeO-C6H4
2-Naphthyl
3-Pyridyl
Ph
We explored the transformations of cycloaddition adduct
4a. As outlined in Scheme 4, the dehydrogenation process
9
10
11
H
6-Cl
8-EtO
4j
4k
Ph
a
Reactions were performed with azadiene 2 (0.1 mmol), acetaldehyde
(0.4 mmol), catalyst 1f (0.02 mmol) and benzoic acid (0.02 mmol) at
5 1C for 12–24 h. Then the hemiaminal 3 was isolated and reduced
b
c
to give compound 4. Isolated yield for two steps. Determined
d
by chiral HPLC analysis. The absolute configuration of 4a was
Scheme 2 ADAR of azadiene 2a and propionaldehyde.
determined by X-ray analysis, see Fig. 1.16 The other products were
assigned by analogy.
the aryl ring of the coumarin moiety were also tolerated
(entries 10 and 11).
Based on the X-ray structure of enantiopure 4a (Fig. 1), a
plausible catalytic mode was proposed to rationalize the
generation of the observed stereocontrol. An endo-selective
Scheme 3 ADAR of azadiene 2a and a,b-unsaturated aldehydes.
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Scheme 4 Synthetic transformations of enamide 4a.
could readily occur by Pd/C catalysis, and the pyridine
derivative 7 was obtained in good yield.8a,17 In addition, the
enamide double bond of 4a could be reduced by Et3SiH/BF3ÁEt2O
when heated at 70 1C in 1,2-dichloroethane (DCE).
Chroman-2-one 8 with three contiguous stereogenic centres
was obtained in excellent diastereoselectivity, while the yield
was fair due to some decomposition of 4a under such harsh
conditions.
In conclusion, we have presented the first example of a
highly enantioselective inverse-electron-demand aza-Diels–
Alder reaction of N-Ts-1-aza-1,3-butadienes derived from
3-argiocarbonylcoumarins and acetaldehyde by employing a
bulky chiral secondary amine catalyst. An array of substrates
have been applied to afford tricyclic chroman-2-one derivatives
incorporating a piperidine motif in high enantioselectivities
and yields. In comparison with 2,4-disubstituted 1-azadienes,
some different reaction patterns have been noted for the
azadienes from 3-argiocarbonylcoumarins in other amino-
catalytic aza-Diels–Alder reactions. Currently, further studies
are underway in our group and the results will be reported in
due course.
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We are grateful for financial support from the National
Natural Science Foundation of China (20972101), PCSIRTC
(IRT0846) and National Basic Research Program of China
(973 Program) (2010CB833303).
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Chem. Commun., 2010, 46, 2665–2667 | 2667