Enantioselective organocatalytic reactions of 4-hydroxy-coumarin and 4-hydroxypyrone with α,β-unsaturated aldehydes - An efficient Michael addition-acetalization cascade to chromenones, quinolinones and pyranones

Article abstract of DOI:10.1002/adsc.200800340

An efficient, organocatalytic enantioselective addition-cyclization reaction of cyclic 1,3-dicarbonyl compounds with different α,β- unsaturated aldehydes has been developed. The diarylprolinol ether-catalyzed reaction cascade provides a variety of chromenones, quinolinones and pyranones in good yields and with excellent enantioselectivities.

Full text of DOI:10.1002/adsc.200800340

UPDATES
DOI: 10.1002/adsc.200800340
Enantioselective Organocatalytic Reactions of 4-Hydroxy-
coumarin and 4-Hydroxypyrone with a,b-Unsaturated Aldehydes
ACHTREUNG
– An Efficient Michael Addition-Acetalization Cascade to
Chromenones, Quinolinones and Pyranones
Magnus Rueping,a,* Estíbaliz Merino,a and Erli Sugionoa
a
Institute of Organic Chemistry and Chemical Biology, University of Frankfurt, Max-von-Laue Strasse 7, 60438 Frankfurt,
Germany
Fax : (+49)-69-798-29248; e-mail: M.Rueping@chemie.uni-frankfurt.de
Received: June 2, 2008; Published online: August 25, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800340.
Abstract: An efficient, organocatalytic enantiose-
lective addition-cyclization reaction of cyclic 1,3-di-
carbonyl compounds with different a,b-unsaturated
aldehydes has been developed. The diarylprolinol
ether-catalyzed reaction cascade provides a variety
of chromenones, quinolinones and pyranones in
good yields and with excellent enantioselectivities.
procedure for the synthesis of pyranocoumarins, chro-
menones, quinolinones and pyranones starting from
readily available cyclic 1,3-dicarbonyl compounds and
a,b-unsaturated aldehydes.
Recently, we described for the first time the devel-
opment of a general and practical organocatalytic
enantioselective addition-cyclization cascade of 2-hy-
droxynaphthoquinone with a,b-unsaturated aldehydes
(Scheme 1). This efficient diarylprolinol ether-cata-
lyzed reaction provided pyranonaphthoquinones in
good yields and with excellent enantioselectivities.[2]
Additionally, we were able to extend this procedure
to the catalytic enantioselective synthesis of benzopyr-
ans and chromenes employing different 1,3-dike-
tones.[3]
Keywords: Brønsted acids; diarylprolinol ethers;
domino reaction; iminium catalysis; pyranocoumar-
ins
Coumarin derivatives are widely distributed in nature.
Based on this strategy and our interest in the devel-
Especially pyranocoumarins, whose principal core, the opment of organocatalytic domino and cascade reac-
pyrano
ACHTREUNG
found in a variety of natural products, and is used as anocoumarins started with the diarylprolinol ether-
a versatile intermediate in organic and natural prod- catalyzed reaction of 4-hydroxycoumarin 1 with trans-
uct synthesis. Moreover, this class of compound is re- 2-hexenal 2b.[5] The effects of catalyst loading, solvent,
ported to have various biological activities, such as and temperature on the enantioselectivity of these re-
antimalarial, antibacterial, anticoagulant and anti- actions are summarized in Table 1. As shown in
HIV activities.[1] Consequently, the development of an Table 1, lower catalyst loadings resulted in slightly re-
efficient synthesis to obtain these valuable com- duced enantioselectivities (Table 1, entries 3–5). Fur-
pounds has attracted our interest. Here we report the ther reaction optimization focused on the choice of
development of a new asymmetric, organocatalytic reaction media. The reactions proceeded smoothly in
Scheme 1. Diarylprolinol ether-catalyzed enantioselective addition cyclization cascade reaction.
Adv. Synth. Catal. 2008, 350, 2127 – 2131
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Magnus Rueping et al.
UPDATES
Table 1. Influence of the solvent, catalyst loading and tem-
perature on the enantioselectivity.
Table 2. Substrate scope of the new addition-cyclization cas-
cade.
Entry[a]
4
mol% of Solvent Temperature
[8C]
ee
Entry[a] Catalyst
R
Product Yield ee
3
4
[%][b]
4
[%][d] [%][e]
1
2
3
4
5
6
7
8
9
4a 20
4b 20
4b 20
4b 10
4b 5
4b 20
4b 20
4b 20
4b 20
CH2Cl2 10
CH2Cl2
92
84
90
88
85
95
87
94
90
1
4a
4a
4b
4a
4b
4a
4a
4b
4a
4a
4a
4a
C2H5
C3H7
C3H7
C4H9
3a
3b
3b
3c
3c
3d
3e
3e
3f
3g
3h
83
85
83
81
63
89
80
76
41
82
45
57
93
92
95
93
94
91
95
92
89
92
94
94
0
2
CH2Cl2 ꢀ20
CH2Cl2 ꢀ20
CH2Cl2 ꢀ20
toluene ꢀ20
DMSO ꢀ20
3[b]
4
5[b]
6
C4H9
C7H15
C10H21
C10H21
Ph
2-Br-C6H4
4-Br-C6H4
7
Et2O
Bu2O
ꢀ20
ꢀ20
8[b]
9[c]
10
11[c]
12[c]
[a]
Reactions were performed with 4-hydroxycoumarin 1
(1.0 equiv.) and aldehyde 2b (1.3 equiv.).
Determined by HPLC analysis.
[b]
4-MeO-C6H4 3i
[a]
Reactions were performed with 4-hydroxycoumarin 1
(1.0 equiv.), aldehyde 2 (1.5 equiv.) and catalyst 4 (20
mol%).
various solvents in the presence of diarylprolinol
ether 4.[6,7] While the polarity of the solvent appeared
to have only a minimum effect on the enantioselectiv-
ity (Table 1, entries 3, 6–9), the reaction temperature
showed a noticeable impact on the enantiomeric
excess observed (Table 1, entry 2 vs. entry 3). With
catalyst 4b the highest enantioselectivity was achieved
when the reaction was carried out in toluene at
ꢀ208C (Table 1, entry 6). However, comparable re-
sults could also be obtained with catalyst 4a in di-
chloromethane at 108C (Table 1, entry 1).
[b]
[c]
[d]
[e]
Performed in toluene at ꢀ208C for 50 h.
In MeCN.
Yield of isolated products after column chromatography.
Enantiomeric excess was determined by chiral HPLC.
Table 3. Influence of the solvent, catalyst loading, and tem-
perature on the enantioselectivity of the diphenyl prolinol
ether catalyzed reaction cascade.
Having established the optimal reaction conditions
for the reaction of 4-hydroxycoumarin 1 with a,b-un-
saturated aldehydes 2, we decided to explore the
scope of substrates by employing a range of aliphatic
and aromatic a,b-unsaturated aldehydes. The results
are summarized in Table 2. In general, the addition-
cyclization reaction proceeded well affording the pyr-
anocoumarins 3 in moderate to good isolated yields
and with high enantioselectivities (89–95% ee).
Entry[a]
4
mol% of Solvent Temperature
[8C]
ee
4
[%][b]
To explore further the potential of this addition-
cyclization cascade[8] we decided to use other cyclic
1,3-dicarbonyl compounds, such as the 4-hydroxy-6-
methyl-2-pyrone 5. Table 3 shows the optimization of
the diarylprolinol ether-catalyzed reaction of pyrone 5
with trans-2-hexenal 2b. Again dichloromethane was
found to be the solvent of choice and product 6b was
isolated with high enantioselectivities (Table 3, en-
tries 2–5). A slight loss of enantiomeric excess was ob-
served when the catalyst loading was decreased
(Table 3, entry 3 vs. entry 2). However, lowering the
reaction temperature from 108C to 08C improved the
1
2
3
4
5
6
7
8
9
4b 20
4a 20
4a 10
4a 10
4a 20
4a 20
4a 20
4a 20
4a 20
CH2Cl2 10
CH2Cl2 10
CH2Cl2 10
64
92
88
91
90
88
65
78
80
CH2Cl2
0
CH2Cl2 r.t.
Toluene r.t.
DMSO r.t.
DMF
r.t.
CH3CN r.t.
[a]
Reactions were performed with pyrone 5 (1.0 equiv.), al-
dehyde 2b (1.3 equiv.) and catalyst 4.
Determined by HPLC analysis.
[b]
2128
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2127 – 2131

Enantioselective Organocatalytic Reactions of 4-Hydroxycoumarin and 4-Hydroxypyrone
UPDATES
Table 4. Substrate scope of the organocatalytic enantioselec-
tive addition-cyclization cascade.
action was conducted with 10 mol% of diarylprolinol
ether 4a in dichloromethane at 08C (Table 3, entry 4).
With this optimized reaction protocol in hand, we
explored the scope of our methodology using 4-hy-
droxy-6-methyl-2-pyrone 5 and a variety of a,b-unsa-
turated aldehydes 2. As shown in Table 4, the reaction
generally proceeds with both aliphatic and aromatic
a,b-unsaturated aldehydes yielding various pyranones
6 in moderate to good yields and with good to excel-
lent enantioselectivities (Table 4).
Pyranocoumarins 3 are not only important, biologi-
cally interesting substrates but can also easily be used
as valuable intermediates for the synthesis of pharma-
cologically active compounds. For instance, the oxida-
tion of 3b with PCC in dichloromethane at ambient
temperature afforded the lactone 7b without a consid-
erable loss of enantiomeric excess (Scheme 2). Addi-
tionally, employing reductive conditions the pyrano-
coumarin 3b can be directly transformed to the cyclic
ether 8b in good yields. Again, no significant loss of
enantiomeric excess was observed.
Entry[a]
6
R
Yield [%][d]
ee [%][e]
1
2
3
4
6a
6b
6c
6d
6e
6f
6g
6h
6i
C2H5
C3H7
C4H9
C7H15
C10H21
Ph
4-MeO-C6H4
2-Cl-C6H4
4-Br-C6H4
82
86
74
96
59
56
43
48
55
92
91
91
90
91
83
85
5
6[b]
7[c]
8[c]
9[c]
80 (95)[f]
84
[a]
Reactions were performed with pyrone 5 (1.0 equiv.), al-
dehyde 2 (1.5 equiv.), 60 h.
96 h at room temperature.
[b]
[c]
[d]
[e]
[f]
48 h at room temperature.
The new addition-acetalization reaction can also be
utilized for the reaction of 4-hydroxy-1-methyl-1,2-di-
Yield of isolated product after column chromatography.
Enantiomeric excess was determined by HPLC.
After one recrystallization from CH2Cl2.
hydroquinolin-2-one
9
with trans-2-heptenal 2c.
Again, the reaction proceeded smoothly with 20
mol% catalyst 4a in dichloromethane at ambient tem-
enantioselectivity considerably (Table 3, entry 3 vs. perature to give the corresponding product which
entry 4). Further evaluation of the reaction parame- after subsequent oxidation with PCC resulted in the
ters revealed that the best results with regard to both desired quinolinone 10 with an acceptable enantio-
selectivity and reactivity were achieved when the re- meric excess of 89% (Scheme 3).
The carbazole-containing pyranocoumarin 11 has
been shown to have excellent anticoagulant proper-
ties.[9] Therefore, we decided to prepare 11 using our
newly developed procedure. Hence, the diarylprolinol
ether 4a catalyzed reaction of cinnamaldehyde with 4-
hydroxycoumarin 1 afforded the desired pyranocou-
marin 3f which after subsequent reaction with carba-
zole resulted in the first enantioselective synthesis of
11 (Scheme 4).
The constitution and absolute configuration of the
pyranocoumarins 3 was determined by single X-ray
crystal structure analysis of 3g. On the basis of this
structure compound 3 was assigned to have (R)-con-
figuration (Figure 1).
In summary, we have developed an efficient and
highly enantioselective addition-cyclization cascade in
Scheme 2. Transformation of pyranocoumarin 3b in the cor-
responding lactone 7b or cyclic ether 8b.
Scheme 3. Enantioselective synthesis of quinolinone 10.
Adv. Synth. Catal. 2008, 350, 2127 – 2131
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Magnus Rueping et al.
UPDATES
Scheme 4. Enantioselective synthesis of carbazole substituted pyranocoumarin 11.
General Procedure
A screw-capped test tube equipped with a stir bar was
charged with aldehyde (1.30 equiv.), catalyst (0.02 equiv.)
and solvent (0.20M) at the temperature indicated. The
cyclic 1,3-dicarbonyl compound (1.00 equiv.) was then
added. The mixture was allowed to stir at the temperature
indicated for 48–96 h. The crude reaction mixture was di-
rectly subjected to column chromatography (hexane:ethyl
acetate, 5:1 ! hexane:ethyl acetate, 1:1) on silica gel to
afford the corresponding product.
The characterization data for the compounds made is
available in the Supporting Information.
Acknowledgements
We gratefully acknowledge Evonik Degussa and the DFG
(Priority Programme Organocatalysis) for generous support
and the Ministerio de Educación y Ciencia, Spain, for a sti-
pend given to E.M.
Figure 1. X-ray crystal structure of pyranocoumarin 3g.
which various different cyclic dicarbonyl compounds
and a,b-unsaturated aldehydes can successfully be
employed. The attractive features of this new diaryl-
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Enantioselective Organocatalytic Reactions of 4-Hydroxycoumarin and 4-Hydroxypyrone
UPDATES
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2131