Organocatalytic synthesis of chiral benzopyrans

Article abstract of DOI:10.1016/j.tetasy.2006.06.028

Benzopyrans, or chromenes, are widespread in nature and are considered to be a privileged scaffold in medicinal chemistry. Herein, we report the first organocatalyzed asymmetric synthesis of chiral benzopyrans. The benzopyran unit is constructed through a

Full text of DOI:10.1016/j.tetasy.2006.06.028

Tetrahedron: Asymmetry 17 (2006) 1763–1767
Organocatalytic synthesis of chiral benzopyrans
a
a,b
Thavendran Govender, Leila Hojabri, Firouz Matloubi Moghaddam
b
a,
*
and Per I. Arvidsson
a
Department of Biochemistry and Organic Chemistry, Box 573, SE-751 23 Uppsala, Sweden
Department of Chemistry, Sharif University of Technology, PO Box 11365-9516, Tehran, Iran
b
Received 17 May 2006; accepted 13 June 2006
Available online 25 July 2006
Abstract—Benzopyrans, or chromenes, are widespread in nature and are considered to be a privileged scaffold in medicinal chemistry.
Herein, we report the first organocatalyzed asymmetric synthesis of chiral benzopyrans. The benzopyran unit is constructed through a
domino reaction involving an oxa-Michael attack of salicylic aldehyde derivatives onto a,b-unsaturated aldehydes, activated through
iminium-ion formation with the organocatalyst, followed by an intramolecular aldol reaction and subsequent elimination of water. This
overall reaction sequence provides benzopyrans with aromatic C-2 substituents in up to 60% yield and 60% enantioselectivity, while C-2
aliphatic analogues can be obtained in 90% enantiomeric excess, but with only 20% yield. The role of additives, as well as the possible
racemization of the benzopyran, was also investigated.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
base-catalyzed condensation of 2-hydroxybenzaldehydes
with a,b-unsaturated aldehydes as reported by Br a¨ se et al.
4
The benzopyran, or chromene, structural core is a wide-
spread element in natural products and in lead compounds
with proven pharmacological activities. Certain benzopy-
The latter procedure relies on a substoichiometric amount
(0.5 equiv) of a non-secondary base for increasing the
nucleophilicity of the hydroxybenzaldehyde. We figured
that this synthetic sequence should benefit from an organo-
catalytic activation of the a,b-unsaturated aldehyde
1
rans have also received attention due to their photochromic
2
and thermochromic properties. Many of the biologically
active benzopyrans reported to date belong to the 2,2-di-
methyl-2H-benzopyrans family 1, that is, they lack a stereo-
genic center in the pyran ring, while others possess a
stereogenic center at C-2, that is, 2:
5
,6
through iminium-ion catalysis,
which would allow a
novel entry to C-2 chiral benzopyrans if a chiral catalyst
were to be used. This synthetic sequence would open an
alternative route toward these highly attractive targets,
which in turn will help unravel the stereochemical influence
on these molecules’ biological activity.
R2
O
R1
1
2
R1 = R2 = Me
R1 ≠ R2
2. Results and discussion
We envisaged a reaction sequence in which the iminium-ion
intermediate 4 is first formed through the reaction of a
secondary amine catalyst and the a,b-unsaturated aldehyde
Chiral benzopyrans have been prepared by kinetic resolu-
tion,3 dehydrogenation of chromane, cyclization of an
a
3b
3
c
a,b-unsaturated sulfoxide, and most recently through
3
(Scheme 1). This highly electrophilic compound then
3
d,e
Ru-catalyzed metathesis.
The most recent methodology
undergoes a domino reaction involving an oxa-Michael
addition with the hydroxy-aldehyde, leading to enamine
for the preparation of non-chiral benzopyrans is based on
5
, followed by an intramolecular aldol reaction giving
b-hydroxy-aldehyde 6. Although valuable per se, this
compound is expected to readily undergo elimination lead-
ing to the conjugated benzopyran system 7.
*
0
Corresponding author. Tel.: +46 18 471 3787; fax: +46 18 471 3818;
e-mail: Per.Arvidsson@kemi.uu.se
957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.028

1764
T. Govender et al. / Tetrahedron: Asymmetry 17 (2006) 1763–1767
O
OH
O
N
R
N
N
H
OH
O
O
R
O
O
R
O
R
O
3
R
4
6
5
7
Scheme 1. Proposed organocatalytic synthesis of benzopyrans.
Initially, we set out to investigate the addition of salicyl-
aldehyde 8 and trans-cinnamaldehyde 9 to yield chiral
nor did the MacMillan5a catalyst 14. The novel imidazole
catalyst 15, successful in activating a,b-unsaturated alde-
hydes for nucleophilic attack by nitroalkanes, did not
provide any product. The lack of reactivity for the arche-
typal iminium-ion catalysts 14 and 15 suggests that these
are too bulky to successfully bring about this intramole-
cular domino reaction.
1
0
2
-phenyl-2H-chromene-3-carbaldehyde 10 (Table 1). A
selected number of organocatalysts, that is, 11–16, were
tested for this benchmark reaction:
N
N
N
Ph
Ph
OTMS
N
N
N
H
N
H
N
H
N
H
The effect of acid and base additives on the reaction is
outlined in Table 2. The addition of base was expected to
increase the nucleophilicity of the salicylic aldehyde and
also promote the final elimination of water, which resulted
in formation of the conjugated benzopyran structure.
The use of imidazole (Table 2, entry 1) decreased the rate
of conversion significantly but increased the ee by 9%.
Although the most successful reagent for the non-
asymmetric substoichiometric reaction explored by Br a¨ se,
DABCO decreased the yield and enantioselectivity of the
iminium-catalyzed reaction, possibly by promoting an
unwanted vinylogous aldol reaction leading to tri-cyclic
HN N
1
1
12
13
O
O
N
N
N
Ph
Ph
OH
Ph
N
H
N
H
N
N
H
.
HCl
14
15
16
7
Jørgensen et al. have repeatedly shown that the TMS
protected prolinol derivative 11 is useful for activating
a,b-unsaturated aldehydes for Michael addition reactions,
and the results presented in Table 1 confirm this. Despite
the fact that this catalyst was employed as a free base,
considerable turnover and promising levels of enantioselec-
tivity were observed in dichloromethane (entry 1), while
other solvents gave slower reactions (entries 2–4). Neither
4
a
hemiacetal formation. Likewise, the addition of trans-
2,5-dimethylpiperazine led to a decrease in yield (entry 3).
The addition of acid on the other hand was expected to
facilitate the formation of the activated iminium-ion.
Surprisingly, the use of strong acids such as TFA or p-
toluenesulfonic acid more or less completely inhibited the
reaction (entries 4 and 5), while a weaker acid, such as
p-chlorobenzoic acid, yielded the product with a 12%
8
9
of the tetrazole catalysts 12 and 13 gave any product,
Table 1. Screening of catalysts for the organocatalyzed reaction between salicylaldehyde 8 and trans-cinnamaldehyde 9 yielding 2-phenyl-2H-chromene-3-
carbaldehyde 10
O
Cat. (10 mol%)
Solvent
O
+
O
OH
O
Ph
8
9
10
b
c
Entry
Catalyst
Time (h)
Solvent
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
9
11
11
11
48
64
45
45
67
67
67
67
67
67
64
66
CH
DMF
Toluene
2
Cl
2
90
20
19
6
0
0
5
0
0
0
60
35
nd
nd
—
—
nd
—
—
—
—
22
a
11
CH
CH
2
Cl
Cl
2
2
12
12
13
13
14
14
15
16
2
DMF
CH Cl
DMF
CH Cl
2
2
2
2
1
1
1
0
1
2
DMF
DMF
0
20
CH
2
Cl
2
All reactions were carried out using 8 (1 equiv) and 9 (0.5 equiv) with catalyst (0.05 equiv) at ambient temperature.
a
0
ꢁC.
b
c
1
Determined by H NMR.
Determined by Daicel AS-H column, hexane–isopropanol (97:3), flow = 0.8 ml min
À1
.

T. Govender et al. / Tetrahedron: Asymmetry 17 (2006) 1763–1767
1765
Table 2. Investigation into how basic or acidic additives affect the reaction between 8 and 9 catalyzed by 11
a
b
Entry
Time (h)
Additive
Conversion (%)
ee (%)
1
2
3
4
5
6
7
67
67
67
67
67
40
67
Imidazole
DABCO
trans-2,5-Dimethylpiperazine
TFA
p-TsOH
10
43
34
10
0
69
43
7
nd
nd
72
72
p-Chlorobenzoic acid
p-Chlorobenzoic acid
29
52
All reactions were carried out using 1 equiv of the additive with respect to the catalyst (10% as compared to the limiting reagent).
a
1
Determined by H NMR.
b
À1
.
Determined by Daicel AS-H column, hexane–isopropanol (97:3), flow = 0.8 ml min
increase in enantioselectivity, albeit with lower yield. The
be expected to be better Michael acceptors than cinnam-
aldehyde 9, led to a decrease in both isolated yields and
enantioselectivity. The use of the aliphatic substrate 2-hex-
enal 20 resulted in very poor yields; however, the product
was isolated in excellent enantiomeric excess (90%). We
also tried to increase the yield by making the salicylalde-
hyde 8 the limiting reagent; however, this led to by-product
formation (possibly through self-condensation) especially
when aliphatic aldehyde 20 was used. We then performed
the reaction by adding 4 equiv of 2-hexenal 20 in 20 por-
tions over 24 h (entry 9). This not only increased the yield
slightly, but also decreased the product’s ee.
use of p-chlorobenzoic acid not only decreased the rate
1
of formation of 10 as monitored by H NMR, but also
decreased the rate of conversion of 9 into unwanted side
products. The effect of additives suggests that there is a fine
balance between promoting and obstructing the various
reaction steps involved in the desired domino reaction
and in the reactions pathways leading to unwanted side
products.
Br a¨ se has already shown that an increased yield can be
obtained by using the more electron rich 5-methoxy salicyl-
aldehyde 17 instead of salicylaldehyde 8 as the nucleophile
4
a
in the oxa-Michael addition. This led us to investigate the
use of derivatives of the reactants that would favor the
oxa-Michael addition. We found that the use of 5-methoxy
salicylaldehyde 17 resulted in a much faster reaction, with
higher isolated yields but at the expense of enantioselecti-
vity (Table 3, entries 1 and 2). Surprisingly, the use of
nitro-substituted cinnamaldehydes 18 and 19, which would
Concerning the mechanism of this reaction, we failed to
observe intermediates 5 and 6 via NMR. However, we were
able to detect the rapid formation of iminium-ion 4. Con-
sequently, we do not expect the iminium-ion formation to
be rate determining in this reaction, as suggested by the
lack of rate enhancement in the presence of an acid (Table
2). Thus, it appears that the oxa-Michael reaction is the
Table 3. Scope of the organocatalyzed synthesis of chiral benzopyrans
R1
R1
O
1
1 (10 mol%)
O
+
R2
O
OH
2
CH Cl2
O
R2
9
1
1
2
R = Phenyl
2
8
1
R = H
R1
H
R2
1
8 R2 = p-Nitrophenyl
9 R2 = o-Nitrophenyl
0 R2 = propyl
7 R1 = OMe
10
Phenyl
2
2
2
2
2
2
1
2
3
4
5
6
OMe Phenyl
H
H
p-Nitrophenyl
o-Nitrophenyl
OMe o-Nitrophenyl
H
propyl
OMe propyl
Entry
Product
Time (h)
Isolated yield (%)
ee (%)
1
2
3
4
5
6
10
21
22
23
24
25
25
26
26
48
36
48
48
36
16
24
16
16
63
70
36
28
54
14
25
15
21
60
44
48
27
29
77
69
90
90
a
7
8
9
b
All reactions were carried out with 8/17 (2 equiv), the a,b-unsaturated aldehyde (1 equiv) and catalyst 11 (10 mol %) at room temperature for a maximum
of 48 h or until 100% conversion of the limiting reagent. See Ref. 12 for a typical procedure.
a
Cat. amount of p-chlorobenzoic acid added.
b
2-Hexenal (4 equiv) was added portionwise.

1766
T. Govender et al. / Tetrahedron: Asymmetry 17 (2006) 1763–1767
rate-determining step in this reaction. This assumption is
supported by NMR and GC–MS investigations of the reac-
tion mixture showing that the amount of salicylaldehyde is
conserved either as starting material or product throughout
the reaction, while the a,b-unsaturated aldehyde is con-
sumed in some type of self-condensation (presumably via
a vinylogous aldol reaction) and/or hemiacetal formation
that inhibits an efficient activation through reaction with
the catalyst.
nism, and the findings concerning the stereochemical integ-
rity of the benzopyran suggest that an even more effectual
process may be obtained by careful optimization of the
reaction conditions involved.
Acknowledgments
We are grateful to Vetenskapsr a˚ det (The Swedish Research
Council) for financial support. T.G. acknowledges the
Wenner-Gren foundation for a postdoctoral fellowship,
and L.H. acknowledges the Swedish Institute (SI) for a
scholarship.
Benzopyrans are known to undergo photochemical and
thermal racemization via opening and closing of the bicy-
2
,3e
clic framework (Scheme 2).
This racemization has also
been proposed to account for the finding that many natu-
3
e
rally occurring benzopyrans are isolated as racemates.
To investigate whether photoinduced racemization was a
problem under the reaction conditions employed in the
present investigation, we subjected benzopyran 25 to white
light and heat from a desk lamp for 48 h. The solution
turned from light green to light orange and the enantio-
meric excess of the product dropped from 90% to 71%.
This is quite a modest drop in enantiomeric excess, when
compared to the fast racemization observed by Wipf
References
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e
et al. for a benzopyran lacking C-3 substitution. We sus-
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mization was observed by Malinakova et al. for benzo-
2
1
1
pyrans with ester-substitution at both C-2 and C-3.
(
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precautions should be taken if the products are to be
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Organic Photochromic and Thermochromic Compounds;
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O
O
uv/heat
O
R2
O
R2
Scheme 2. Photochemical and thermal excitation are known to cause
racemization of unsubstituted benzopyrans. The carbonyl group at the
C-3 position apparently slows this process down.
4
3
. Conclusion
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In conclusion, we have shown that chiral benzopyrans, also
known as chromenes, can be successfully synthesized
through an organocatalytic domino reaction sequence con-
sisting of iminium-ion activation of an a,b-unsaturated
aldehyde, followed by intermolecular oxa-Michael addition
of a salicylic aldehyde derivative. The intermediate
enamine thus formed undergoes an intramolecular aldol
reaction, which upon elimination of water leads to the
desired benzopyran core containing a chiral center at C-2.
These products contain several functionalities that allow
further transformations into even more complex entities,
but are also highly valuable molecules themselves, due to
their widespread occurrence in Nature and as privileged
scaffolds in medicinal chemistry. Although the present
organocatalytic route has limitations in terms of yields
and stereoselectivities, it still measures up as one of the
most efficient methods around for constructing C-2 chiral
benzopyrans from readily available starting material.
Moreover, the preliminary studies on the reaction mecha-
6
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1767
1
required time. Pure product was obtained after chromatog-
raphy (silica gel, diethyl ether–pentane). All the products are
light green in color and their migration through the column
can be easily monitored. The following is a list of solvent
systems used for flash chromatography given in the ratio of
diethyl ether–pentane. Compounds 15 and 21 (0.5:9.5), 22–24
(1:1), 25 and 26 (0.25:9.75). Enantioselectivities were deter-
mined using a Chiralpak AS-H column (0.46 cm · 25 cm),
9
6
11.
1
1
0. Hojabri, L.; Moghaddam, F. M.; Arvidsson, P. I., submitted
for publication.
1. (a) Portscheller, J. N.; Lilley, S. E.; Malinakova, H. C.
Organometallics 2003, 22, 2961; (b) Lu, G.; Malinakova, H.
C. J. Org. Chem. 2004, 69, 4701.
À1
flow of 0.8 ml min ; compounds 15, 21, 25, and 26 required
1
2. Typical reaction conditions. Salicylaldehyde (1 mmol), cin-
namaldehyde (0.5 mmol), and catalyst (0.05 mmol) in dry
DCM (0.5 ml) were stirred at ambient temperature for the
a mobile phase of 97:3 hexane–isopropanol and 22–24
required a mobile phase of 80:20 hexane–isopropanol for
separation.