Catalytic asymmetric mannich-ketalization reaction: Highly enantioselective synthesis of aminobenzopyrans

Article abstract of DOI:10.1002/chem.201000203

"Chemical Equation Present" Domino catalysis: We have developed the first enantioselective domino Mannich-ketalization reaction of o-hydroxy benzaldimines with electron-rich alkenes (see scheme). The new reaction sequence provides an easy and direct acces

Full text of DOI:10.1002/chem.201000203

COMMUNICATION
DOI: 10.1002/chem.201000203
Catalytic Asymmetric Mannich–Ketalization Reaction: Highly
Enantioselective Synthesis of Aminobenzopyrans
Magnus Rueping* and Ming-Yuan Lin[a]
The benzopyran structure is present in a number of natu-
rally occurring products with interesting biological activi-
ties,[1] including antihypertensive and anti-ischemic behav-
ior.[2] 4-Aminobenzopyran derivatives can also be used as
modulators of potassium channels affecting cardiac activity
of the blood pressure.[3] Owing to the importance of the ben-
zopyran framework, their synthesis has attracted considera-
ble attention.[4] Although several Lewis acids have been em-
ployed as catalysts to afford benzopyran derivatives, to the
best of our knowledge, there is no report of a direct catalytic
asymmetric method for the synthesis of optically active 4-
aminobenzopyran derivatives.[5] Thus, the development of a
new catalytic asymmetric method for their preparation at-
tracted our interest.
Over the past few years, asymmetric organocatalysis has
emerged as a powerful tool for a variety of organic transfor-
mations. In this context, organocatalytic domino reactions
are of particular interest as more than one stereocenter can
be formed in a single reaction sequence.[6] Thus we decided
to examine the enantioselective domino reaction of o-hy-
droxybenzaldimines with 3,4-dihydro-2H-pyran (DHP) and
2,3-dihydro-2H-furan (DHF). This would not only be the
first example of a direct asymmetric catalytic variant of such
a reaction but more importantly it would give direct and
ready access to enantiomerically enriched 4-aminobenzopy-
Scheme 1. A Mannich–ketalization reaction for the synthesis of 4-amino-
benzopyrans.
lysts in the Mannich–ketalization reaction of o-methoxybenz-
AHCTUNGTREGaNNNU ldimine with 2,3-dihydro-2H-furan. The best results with
regard to reactivity and selectivity were obtained with the
highly acidic N-triflylphosphoramides (Table 1).[8] These had
earlier been introduced by Yamamoto et al.[9a] but have sur-
prisingly not yet been widely applied in asymmetric cataly-
sis.[9]
Table 1. Evaluation of chiral N-triflylphosphoramide catalysts in the
enantioselective domino Mannich–ketalization reaction.
ACHTUNGTRENNUNG
of 4-aminobenzopyranes and derivatives through an enan-
tioselective Mannich[7]–ketalization reaction (Scheme 1).
On the basis of our previous work in the field of chiral
counterion and domino catalysis, we initially started our in-
vestigation with the exploration of various metal free cata-
Entry[a]
Ar
Yield [%][b]
d.r.[c]
e.r.[d]
1
2
3
4
5
6
phenyl (1a)
88
85
75
85
90
69
78
80
1.1:1
1.5:1
1:1
60:40
80:20
60:40
59:41
60:40
79:21
86:14
12:88
1-naphthyl (1b)
2-naphthyl (1c)
4-F-C6H4 (1d)
4-OMe-C6H4 (1e)
9-anthracenyl (1 f)
9-phenanthryl (1g)
9-phenanthryl (1h)
1:1
1.1:1
1.3:1
1.15:1
1.2:1
7
[a] Prof. Dr. M. Rueping, Dr. M.-Y. Lin
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-92665
8[e]
[a] Reaction conditions: 2a, 3 (5.0 equiv), 1 (5 mol%), 0.25m solution in
1,2-dichloroethane (DCE) at À108C. [b] Yield of isolated product after
chromatography. [c] Determined by 1H NMR spectroscopy. [d] Deter-
mined by HPLC analysis. [e] Use S enantiomer of 1g yields in the oppo-
site enantiomer 4a’.
E-mail: Magnus.Rueping@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000203.
Chem. Eur. J. 2010, 16, 4169 – 4172
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4169

The best results with regard to diastereo- and enantiose-
lectivity were obtained with catalytic amounts of 1g
(5 mol%) providing 4-aminobenzopyran (4a) with an enan-
tiomeric ratio of 86:14 in favor of the cis-isomer (Table 1,
entry 7). Applying chiral N-triflylphosphoramide (1h) de-
rived from (S)-BINOL as the catalyst resulted in the prod-
uct with the opposite configuration.
Subsequently, we examined different reaction parameters
by varying reactant concentrations, solvents, temperatures
and the influence of the aldimine protecting group in order
to improve the enantioselectivity.[10] For instance, several N-
aryl-aldimine derivatives were prepared and tested in the
enantioselective domino Mannich–ketalization reaction. The
results are summarized in Table 2. In general excellent enan-
tiomeric ratios were obtained irrespective of the aryl group
used (Table 2, entry 2–7). The highest enantiomeric ratios
(e.r. 96:4) were obtained with phenyl- and p-methoxyphe-
Scheme 2. Brønsted acid catalyzed reaction of aldimines with dihydrofur-
anes leads depending on the hydroxyl substitution to either formation of
a) tetrahydroquinolines or b) furanobenzopyranes.
ACHTUNGTRENNUNGnyl-protected aldimine derivatives.
With the optimized conditions in hand, we decided to ex-
plore the scope of this new asymmetric domino Mannich–
ketalization reaction yielding tricyclic furanobenzopyrans
with control of three stereocenters. In general differently
substituted o-hydroxybenzaldimines (Table 2) with various
N-aryl residues (Tables 2 and 3) can be effectively reacted
with 2,3-dihydro-2H-furan to give the desired products in
good yields and with excellent enantioselectivities.
Table 2. Evaluation of different N-aryl aldimines.
The molecular structure of the products was determined
by X-ray analysis of 6h (Figure 1). The absolute configura-
tion of the major diastereomer was assigned to be 3R,4R,9S.
Encouraged by these results we proceeded to examine ad-
ditionally the use of 3,4-dihydro-2H-pyran (8) in this new
catalytic asymmetric Mannich–ketalization reaction.[14] This
Entry[a]
R
t [h]
Yield [%][b]
d.r.[c]
e.r.[d]
1
2-OMe
H
4-OMe
4-Cl
4-F
4-Br
4-Me
24
36
72
60
52
50
55
80 (4a)
81 (4b)
51 (4c)
84 (4d)
76 (4e)
86 (4 f)
74 (4g)
1.2:1
2.7:1
2.5:1
2.3:1
2.1:1
2.3:1
2.6:1
88:12
96:4
96:4
95:5
95:5
94:6
95:5
2[e]
3[f]
4
5
6
7
Table 3. Scope of the Brønsted acid catalyzed enantioselective domino
Mannich–ketalization reaction.
[a] Reaction conditions: 2, 3 (5.0 equiv), 1h (5 mol%), 0.25m solution in
DCE at À108C. [b] Yield of isolated product after chromatography.
1
[c] Determined by H NMR spectroscopy. [d] Determined by HPLC anal-
ysis. [e] The reaction was carried out at À208C. [f] 10 equiv of 3.
The latter observation is particularly interesting if com-
Entry[a]
R
R1
Yield [%][b]
d.r.[c]
e.r.[d]
pared to the recently reported chiral phosphoric acid[11,12]
-
1
2
3
4
5-Cl
5-Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Cl-C6H4
PMP
PMP
PMP
PMP
83 (6a)
87 (6b)
81 (6c)
89 (6d)
88 (6e)
46 (6 f)
87 (6g)
78 (6h)
53 (6i)
51 (6j)
59 (6k)
55 (6l)
1.9:1
2.2:1
1.7:1
1.9:1
96:4
96:4
96:4
95:5
98:2
92:8
87:13
93:7
95:5
94:6
94:6
91:9
catalyzed reverse electron-demanding aza-Diels–Alder reac-
tion by Akiyama and co-workers.[13] The activation of the al-
dimine in this transformation is believed to proceed through
a bifunctional activation via a nine-membered hydrogen-
bonded transition state TS 1 which results in the formation
of the 8-hydroxytetrahydroquinolines (Scheme 2a). In con-
trast, our newly developed N-triflylphosphoramide catalyzed
Mannich–ketalization reaction selectively yields 4-amino-
furanobenzopyrans and is most likely to proceed through
the formation of an intermediary chiral iminium ion pair
transition state (Scheme 2b). Compared to the tetrahydro-
quinoline synthesis the difference in regioselectivity must be
due to the nucleophilicity of the benzaldimine hydroxyl
group which leads to a faster ketalization reaction.
5-OMe
5-Me
4,6-(Cl)2
4-OMe
3-OEt
5-Cl
5-OMe
5-Cl
5-Br
5[e]
6[e]
7[e]
8[e]
9[e,f]
10[f,g]
11[f,g]
12[f,g]
-
[h]
1.8:1
2.1:1
2.2:1
1.2:1
1.15:1
1.5:1
1.3:1
5-Me
[a] Reaction conditions: 5, 3 (5.0 equiv), 1h (5 mol%), 0.25m solution in
DCE at À208C for 30–72 h. [b] Yield of isolated product after chroma-
tography. [c] Determined by 1H NMR-spectroscopy. [d] Determined by
HPLC analysis. [e] At À108C. [f] 10 equiv of 3. [g] At 08C. [h] Only syn
isomer detected.
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Chem. Eur. J. 2010, 16, 4169 – 4172

Asymmetric Mannich–Ketalization Reaction
COMMUNICATION
triflylphosphoramide catalyst and represent a first example
of a Mannich–ketalization reaction in asymmetric domino
catalysis.
Acknowledgements
The authors acknowledge the DFG (Priority Programme Organocataly-
sis) for financial support and the Alexander von Humboldt-Foundation
for a stipend given to M.-Y. Lin.
Keywords: Brønsted acid · chromene · domino reactions ·
ion pairs · organocatalysis
Figure 1. Molecular structure of furanobenzopyran 6h.
would be the first example of the catalytic enantioselective
synthesis of optically pure 4-amino pyranobenzopyrans.
Again diverse o-hydroxy benzaldimines with electron-with-
drawing and electron-donating substituents underwent the
enantioselective domino Mannich–ketalization reaction to
give the desired products 9a–g in good yields with high
enantiomeric ratios (Table 4).
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Entry[a]
R
R1
Yield [%][b]
d.r.[c]
e.r.[d]
1
2
3
4
5
6
7
H
5-Cl
Ph
Ph
Ph
Ph
Ph
Ph
p-Cl-C6H4
65 (9a)
66 (9b)
63 (9c)
69 (9d)
59 (9e)
71 (9 f)
65 (9g)
6.8:1
7.5:1
4.3:1
4.8:1
6.3:1
33:1
21:1
95:5
94:6
94:6
94:6
93:7
97.5:2.5
93:7
5-Br
5-OMe
5-Me
4,6-(Cl)2
H
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[a] Reaction conditions: 2b or 5, 8 (10.0 equiv), 1h (5 mol%), 0.25m so-
lution in DCE at 08C. [b] Yield of isolated product after chromatography.
1
[c] Determined by H NMR spectroscopy. [d] Determined by HPLC anal-
ysis.[14]
In summary, we have developed the first enantioselective
domino Mannich–ketalization reaction of o-hydroxy benzal-
dimines with electron-rich alkenes. The new reaction se-
quence provides an easy and direct access to optically pure
4-aminobenzopyrans in good yields with excellent enantio-
meric ratios (up to e.r. 98:2). Our newly developed reaction
nicely complements Akiyama’s previously reported Brønst-
ed acid catalyzed reaction of aldimines with dihydrofurans
and dihydropyrans which lead to tetrahydroquinolines.
However, our reaction results in the enantioselective synthe-
sis of biologically relevant furanobenzopyrans and pyrano-
benzopyrans. The reaction sequence proceeds under mild re-
action conditions in the presence of an air-stable chiral N-
Chem. Eur. J. 2010, 16, 4169 – 4172
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4171

M. Rueping and M.-Y. Lin
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[14] The use of acyclic vinyl ether such as ethyl vinyl ether was less effec-
tive (88% yield, d.r. 4:1, e.r. 60:40, at 08C).
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Received: January 25, 2010
Published online: March 22, 2010
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Chem. Eur. J. 2010, 16, 4169 – 4172