A quick, clean and green synthesis of methylenedioxyprecocene and other chromenes over basic montmorillonite K10 clay

Article abstract of DOI:10.1055/s-2005-863738

The microwave-assisted, clay-catalyzed condensation of sesamol and other phenols with 3-methyl-2-butenal to give methylenedioxyprecocene 3 and other chromenes, is described.

Full text of DOI:10.1055/s-2005-863738

LETTER
785
A Quick, Clean and Green Synthesis of Methylenedioxyprecocene and other
Chromenes over Basic Montmorillonite K10 Clay
S
ynthesis of Methylen
a
o
t
cene
a
t
nd othe
h
r
Chromene
e
w R. Dintzner,* Thomas W. Lyons, Michael H. Akroush, Paul Wucka, Adam T. Rzepka
Department of Chemistry, DePaul University, 1036 West Belden Avenue, Chicago, IL 60614, USA
Received 21 October 2004
This manuscript is dedicated to Adam T. Rzepka.
Br
Abstract: The microwave-assisted, clay-catalyzed condensation of
O
O
sesamol and other phenols with 3-methyl-2-butenal to give methyl-
enedioxyprecocene 3 and other chromenes, is described.
O
K10
O
O
OH
O
Key words: green chemistry, natural products, Montmorillonite
clay, microwave-assisted, chromenes
CCl4
2
1
100%
DDQ
benzene
21%
, clay
H
As topics like green chemistry1 and diversity-oriented
synthesis2 continue to shape the way chemists think about
the construction of physiologically active compounds, the
development of synthetic methods that promote faster and
cleaner reactions, with regard to selectivity, atom econo-
my and waste reduction, is pivotal. Environmentally be-
nign clays, naturally abundant, inorganic catalysts, are
ideally suited for advancing modern synthetic chemistry:
they are inexpensive, nontoxic, chemically diverse, and
recyclable.3 While clays have already been shown to ef-
fectively catalyze a wide range of chemical reactions,
their application in the synthesis of diverse libraries of
compounds is far from exhausted.4 The use of microwave
irradiation to promote quicker and cleaner chemical reac-
tions is similarly well suited for the advancement of more
environmentally friendly synthesis,5 especially when used
in combination with clays and under solvent-free condi-
tions.6 Herein, we report a quick, clean and green synthe-
sis of methylenedioxyprecocene (3), an insecticide that
exhibits anti-juvenile hormone activity in some insects.7
Our synthesis features the microwave-assisted condensa-
tion of sesamol with 3-methyl-2-butenal (4) over dry clay.
O
O
4
O
3
Scheme 1 Synthesis of methylenedioxyprecocene 3
Given its widespread occurrence in physiologically active
natural products, synthesis of the 2,2-dimethyl-2H-
chromene ring system is fairly well precedented,10 though
the direct condensation of readily available phenols and
a,b-unsaturated aldehydes on clays has not been reported
previously. At the outset of this investigation we pre-
sumed that acidic Montmorillonite K10 clay might pro-
mote electrophilic aromatic addition of 3-methyl-2-
butenal to sesamol to give intermediate 5 (Scheme 2).
Further, at elevated temperature and with the aid of a
Dean–Stark trap, dehydration of 5 might ensue, followed
by an intramolecular hetero-Diels–Alder reaction of the
incipient o-quinone methide species 6 to give the desired
chromene 3 (Scheme 2).
In a recent communication, we reported a facile, clay-cat-
alyzed, one-pot synthesis of 2,2-dimethylbenzopyrans
(e.g. 2, Scheme 1) from phenols, which promises to be of
practical application in the construction of natural and
non-natural products containing this particular functional
motif.8 Synthesis of the insecticide methylenedioxypre-
cocene (3), for example, was accomplished by K10 clay-
catalyzed conversion of sesamol (1) to the corresponding
2,2-dimethylbenzopyran (2) in quantitative yield, fol-
lowed by oxidation of 2 by DDQ (Scheme 1).9 The second
step of this synthesis, neither high yielding nor environ-
mentally friendly, prompted us to consider a more direct
route to 3 from 1: clay-catalyzed condensation with
3-methyl-2-butenal (4).
O
OH
H
O
O
4
O
O
K10
OH
O
1
5
-H2O
O
O
3
O
6
Scheme 2 Proposed mechanism of the clay-catalyzed conversion of
sesamol to 3
SYNLETT 2005, No. 5, pp 0785–0788
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863738; Art ID: S10404ST
© Georg Thieme Verlag Stuttgart · New York

786
M. R. Dintzner et al.
LETTER
Table 1 Conversion of Sesamol (1) to Methylenedioxyprecocene (3) under Various Conditions
Product distribution (%)a
Conditions
Entry Catalyst
Solvent
Toluene
None
None
None
None
None
None
None
None
None
None
Temp (°C)/energy Time (min)
3
1
Otherb
1
2
K10
Reflux
110
30
120
45
8
19
7
9
3
72
90
0
K10
3
K10
23
3
97
2
4
K10
MWI
110
29
91
84
2
69
9
5
K10-K+
K10-K+
None
60
8
0
6
MWI
MWI
MWI
MWI
MWI
MWI
16
98
31
34
66
92
0
7
8
0
8
K2CO3
Na2CO3
Li2CO3
CaCO3
10
10
10
10
67
66
28
7
2
9
0
10
11
6
1
a Assessed by GC-MS analysis of crude reaction mixture.
b Unidentified.
Upon refluxing a mixture of Montmorillonite K10 clay, ence of microwave irradiation, might allow for a quicker
sesamol (1), and 3-methyl-2-butenal (4) in toluene for 30 and cleaner synthesis of 3 since others had shown this re-
minutes (with Dean–Stark trap), however, we observed action to proceed well in the presence of other (less envi-
only 19% conversion to the desired chromene 3 (mea- ronmentally friendly) bases.10 Indeed, we observed a
sured by GC-MS, Table 1, entry 1). Running the experi- dramatic improvement by running the reaction on basic
ment neat, heating the dry reaction mixture in an oven at clay (K10-K+); conversion of 1 to 3 (neat, 110 °C) was
110 °C was also unsuccessful, giving even less conver- complete after one hour with only a small amount of by-
sion to the desired chromene and a greater amount of other product generated (Table 1, entry 5). The reaction was
unidentified products (Table 1, entry 2). We found that similarly successful when run neat in the microwave, pro-
the reaction was much cleaner when run neat at room tem- ceeding to near completion after only eight minutes with
perature, resulting in a 3% conversion to the desired prod- no undesired by-products detected by GC-MS analysis of
uct after only 45 minutes, with no ‘other’ products the crude reaction mixture (Table 1, entry 6). Minimal re-
observed (Table 1, entry 3). Thus, it appeared that selec- action was observed in a control experiment in which the
tive conversion of sesamol (1) to 3 could be achieved, but two reactants were exposed to microwave irradiation in
that prolonged exposure of the reaction mixture to heat the absence of any catalyst (Table 1, entry 7). Although
resulted in the generation of unwanted by-products.
the reaction proceeded relatively well in the presence of a
series of carbonate bases alone (MWI/10 min, Table 1,
entries 8–11) it was neither as complete nor as clean as
with the K10-K+. Evidently, the success of this particular
reaction may be attributed to a synergistic effect between
the basic clay and microwave irradiation; under these con-
ditions the reaction proceeds most quickly and cleanly.
Organic products are separated from the clay by extract-
ing with methylene chloride and/or methanol. The clay is
recycled by treatment with excess saturated aqueous
K2CO3, filtered and dried in an oven at 110 °C for 1–2
hours.
We reasoned that if we could get the reaction to go more
quickly, that it would also proceed more selectively.
Hence we considered replacing conventional heating with
microwave irradiation (MWI), which had been shown to
greatly enhance rates of reaction for a variety of other sys-
tems.6 Indeed, exposure of a mixture of Montmorillonite
K10 clay, sesamol, and 3-methyl-2-butenal to MWI for 8
minutes resulted in a somewhat quicker and cleaner gen-
eration of 3 (Table 1, entry 4), though this hardly consti-
tuted an improvement over existing methodologies.10 At
this point we considered altering the chemical reactivity
of the clay, which ultimately led to success.
In an effort to explore the general scope of this reaction
under the optimized conditions, sesamol was reacted with
other aldehydes, and a variety of other phenols were re-
acted with 3-methyl-2-butenal (Table 2). Exposure of a
mixture of sesamol, crotonaldehyde, and K10-K+ to
microwave irradiation for eight minutes resulted in about
In its natural form, Montmorillonite K10 clay is Brønsted
acidic, but it can be easily made basic by washing with a
saturated aqueous basic solution (potassium carbonate for
instance). We reasoned that conducting the reaction on
basic K10, either at elevated temperature or in the pres-
Synlett 2005, No. 5, 785–788 © Thieme Stuttgart · New York

LETTER
Synthesis of Methylenedioxyprecocene and other Chromenes
787
Table 2 Reaction Scope
R4
R4
O
R3
R3
R2
H
R6
R5
+
R2
O
R5
R6
OH
R1
R1
8
7
9
Entry
R1
R2
R3
R4
R5
R6
Product distribution (%)
9
7
Other
1
2
3
H
H
H
-O(CH2)O-
-O(CH2)O-
H
H
H
H
CH3
H
48 (9a)11
7 (9b)12
18 (9c)11
11
10
68
41
83
14
H
OCH3
OCH3
CH3
CH3
a 50% conversion to the desired chromene, with only
about 10% unreacted sesamol and 40% by-product
(Table 2, entry 1). Exposure of a mixture of sesamol,
acrolein, and K10-K+ to microwave irradiation for eight
minutes resulted in less than 10% conversion to the de-
sired chromene, with only about 10% unreacted sesamol
and more than 80% by-product (Table 2, entry 2). In both
of the above cases the by-products, not surprisingly,
appeared to result from Michael addition of the phenol to
the unsaturated aldehyde species. The reaction appeared
to be somewhat more general with a variety of phenols
and 3-methyl-2-butenal (entries 3–7 in Table 2), though in
most cases the formation of other, unidentified products
was also observed.
vents were used as purchased from the manufacturer, without
further purification.
General Experimental Procedure for the Synthesis of Methyl-
enedioxyprecocene (3)
A slurry of 500 mg of Montmorillonite K10 clay (Aldrich) in 10 mL
of sat. aq K2CO3 was stirred at r.t. for 1 h. After the clay was allowed
to settle, most of the aqueous phase was decanted off, and the re-
maining clay isolated by vacuum filtration. The wet clay was
washed successively with acetone (to remove excess water) and
CH2Cl2 (to remove residual acetone), then transferred to a round-
bottom flask and evaporated for about 30 min. The dry clay was
transferred to a clean watch glass, where it was spread out and fur-
ther dried in an oven at 110 °C for a period of 1–2 h. The clay was
transferred to a vial, which was fitted with a rubber septum and al-
lowed to cool under nitrogen. In another vial, sesamol (138 mg, 1
mmol) was dissolved in 3-methyl-2-butenal (106 mL, 1.1 mmol). To
this dark solution was added the dried clay and the mixture evenly
distributed using a metal spatula. The vial was placed in the center
of the carousel platform of a household grade microwave oven and
subjected to microwave irradiation for a period of 8 min. The reac-
tion mixture (which had visibly darkened in color) was allowed to
cool to r.t., taken up in 5 mL of CH2Cl2, and filtered to remove the
clay, washing with excess CH2Cl2. Product distribution was mea-
sured by GC-MS analysis. The filtrate was evaporated under vacu-
um to afford a dark oil (176 mg). The crude product was purified by
column chromatography with silica gel, eluting with 90% hexanes–
EtOAc to give 3 as a dark yellow oil (81 mg, 64% yield based on
recovered starting phenol).
In spite of the obvious irony of targeting an insecticidal
compound to demonstrate an example of green synthesis,
the methodology reported herein indeed represents a
quicker and cleaner route to methylenedioxyprecocene
(3). Conditions for the reaction were optimized for the
synthesis of 3 only, but were applied to the construction of
analogous compounds with reasonable success (Table 2).
It is likely that this methodology (solvent-free, basic clay-
mediated, microwave-assisted condensation of phenols
with a,b-unsaturated aldehydes) will be of general appli-
cability in the synthesis of an even wider variety of
chromene-containing compounds, but that conditions
will need to be optimized for each individual system. We
are currently investigating other clay-catalyzed, micro-
wave-assisted reactions for application in the greener syn-
thesis of physiologically active natural and non-natural
products.
Methylenedioxyprecocene (3):10f IR: 3041, 2975, 2892, 2775,
1718, 1645, 1605, 1502, 1482, 1458, 1372, 1361, 1265, 1254, 1199,
1
1158, 1112, 1069, 1039, 904, 859, 818, 776, 757 cm–1. H NMR
(CDCl3): d = 6.49 (s, 1 H), 6.40 (s, 1 H), 6.22 (d, J = 9.75 Hz, 1 H),
5.90 (s, 2 H), 5.50 (d, J = 9.75 Hz, 1 H), 1.49 (s, 6 H). 13C NMR
(CDCl3): d = 148.2, 147.6, 141.4, 128.2, 122.3, 114.3, 105.6, 100.9,
99.1, 76.0, 27.4. GC-MS (70 eV): tR = 9.521 min, m/z (%) = 204,
(33) [M+], 189 (100) [M – 15]+.
1H and 13C NMR spectra were collected at 300 MHz and 75 MHz,
respectively. The proton signal of residual, nondeuterated solvent
(d = 7.26 ppm for CHCl3) was used as an internal reference for 1H
NMR spectra. For 13C NMR spectra, chemical shifts are reported
relative to the d = 77.23 ppm resonance of CDCl3. Coupling
constants are reported in Hz. IR were recorded as thin films on a
Nicolet Avatar 360. GC analysis was performed on a Hewlett
Packard 5890 Series II gas chromatograph with a 5971 Series mass
selective detector. Column chromatography was performed using
Selecto Scientific (70-150 mesh) silica gel. All reagents and sol-
Acknowledgment
We thank the National Science Foundation CCLI A&I program
(Grant No. DUE-0310624) for support in purchasing our Bruker
Avance 300 MHz NMR spectrometer and DePaul University’s
College of Liberal Arts & Sciences for funding and support of this
work.
Synlett 2005, No. 5, 785–788 © Thieme Stuttgart · New York

788
M. R. Dintzner et al.
LETTER
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Synlett 2005, No. 5, 785–788 © Thieme Stuttgart · New York