Direct, regioselective synthesis of 2,2-dimethyl-2H-chromenes. Total syntheses of octandrenolone and precocenes I and II

Article abstract of DOI:10.1016/j.tetlet.2009.06.090

Herein is reported an efficient method for the synthesis of 2,2-dimethyl-2H-chromenes in a single step from the corresponding phenol and 3-methyl-2-butenal via microwave irradiation in CDCl₃. This protocol features a mild reaction environment (neutral, no added catalyst) which yields regioselective formation of the chromene and displays tolerance toward acid- and base-sensitive protecting groups.

Full text of DOI:10.1016/j.tetlet.2009.06.090

Tetrahedron Letters 50 (2009) 5075–5079
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct, regioselective synthesis of 2,2-dimethyl-2H-chromenes. Total syntheses
of octandrenolone and precocenes I and II
b
Marc J. Adler a, , Steven W. Baldwin
*
a Department of Chemistry, Yale University, 225 Prospect St., Box 208107, New Haven, CT 06520-8107, USA
b Department of Chemistry, Duke University, Box 90346, Durham, NC 27708-0346, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein is reported an efficient method for the synthesis of 2,2-dimethyl-2H-chromenes in a single step
from the corresponding phenol and 3-methyl-2-butenal via microwave irradiation in CDCl3. This protocol
features a mild reaction environment (neutral, no added catalyst) which yields regioselective formation
of the chromene and displays tolerance toward acid- and base-sensitive protecting groups.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 January 2009
Revised 16 June 2009
Accepted 17 June 2009
Available online 21 June 2009
Structural motifs which are observed in many naturally occur-
ring organic compounds possessing varying biological activities
have come to be known as ‘privileged structures’.1 One such recur-
ring scaffold is the 2,2-dimethyl-2H-chromene, which appears in a
range of bioactive natural products2 including drummondin A,3,4
rottlerin,5,6 4-hydroxy-3-methoxylonchocarpin,7,8 seselin,9 (ꢀ)-3-
deoxy-MS-II,10 and precocenes I (18) and II (20)11 (Fig. 1).
Over the years, a variety of methods for constructing 2,2-di-
methyl-2H-chromenes have been developed including Grignard
reactions of coumarins, thermal rearrangement of phenyl propar-
This result sparked our interest in developing a method to pre-
pare 2,2-dimethyl-2H-chromenes in a single step from the parent
phenol under conditions which would be compatible with acid-
and base-sensitive protecting groups. Unfortunately, none of the
attempted known methods proved consistently amenable to this
particular operation. Furthermore, the most commonly utilized
methods to effect this general transformation suffer from long
reaction times, the use of dangerous solvents, and/or complicated
reaction setups. To this end, we decided to pursue a detailed inves-
tigation of an uncatalyzed, neutral, microwave-assisted27–30 con-
densation of 3-methyl-2-butenal (1) with substituted phenols as
a novel and direct route to access the family of compounds pos-
sessing this privileged structure.
In an effort to probe the relative reactivities of the selected phe-
nols, each substrate was initially subjected to a set of standard
reaction conditions; the results of these trials are presented in col-
umn 4 of Table 1.31 Each of the explored phenols was chosen be-
cause its corresponding chromene product either is a natural
product or can be taken on to a biologically relevant natural prod-
uct in short order.
gyl ethers, dehydration of corresponding
a-hydroxy- and a-
methoxy-chromanes, oxidation of 2,2-dimethyl-chromanes, and
oxidative cyclization of ortho-prenylated phenols, among others.12
These techniques, however, require multiple steps to access 2,2-di-
methyl-2H-chromenes from the parent phenol. Reaction protocols
have also been established to generate chromenes in a single step
via the thermal,13 base-catalyzed,13–21 or phenylboronic acid-med-
iated22–25 condensation of an
a,b-unsaturated aldehyde with a
phenol. Single-step reactions such as these are believed to generate
a transient ortho-quinone methide intermediate which then under-
goes a 6
p
-electrocyclization in situ to yield the final bicyclic prod-
Several trends were noted, most markedly that increasing the
number of electron-donating groups on the phenol in general in-
creased the effectiveness of this method.
uct as shown in Scheme 1.26
During a synthetic investigation of chromene-containing natu-
ral products, we attempted to utilize one of these methods to con-
struct chromene-containing compound 7. This iodochromane,
obtained via a para-Claisen rearrangement of an O-prenylated pre-
cursor followed by I2-induced cyclization, was subjected to both
aqueous and anhydrous basic conditions, neither of which pro-
vided the desired chromene compound in an acceptable yield
(Scheme 2).
Phloroacetophenone (2) displayed the most striking outcome,
providing the natural product octandrenolone (3) in 89% yield
(Table 1, entry 1). This is a significant improvement on the highest
previously reported yield (40%) of this molecule. While the possi-
bility for formation of two different regioisomeric dichromene
products exists, 3 was the only product observed, the structure
of which was verified by comparison to previously reported spec-
tral data.32 We believe that the hydrogen bonding between the car-
bonyl and the ortho-phenol plays an important role in influencing
the regioselective reaction of this, and all, carbonyl-containing
phenols using this method.
* Corresponding author. Tel.: +1 203 432 8962; fax: 1 203 432 6144.
E-mail address: marc.adler@yale.edu (M. J. Adler).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.090

5076
M. J. Adler, S. W. Baldwin / Tetrahedron Letters 50 (2009) 5075–5079
O
OH
H3CO
O
H3CO
HO
R
O
O
R = H
precocene I (18)
O
O
4-hydroxy-3-methoxylonchocarpin
(electron transport inhibitor)
R = OCH3 precocene II (20)
(anti-juvenile)
O
O
O
HO
O
HO
O
(-)-3-deoxy-MS-II
(antitumor)
OH
OH
OH
OH
O
O
HO
O
O
O
O
OH
OH
rottlerin
(protein kinase C inhibitor)
seselin
(antitumor)
drummondin A
(antibacterial)
Figure 1. Examples of biologically active naturally occurring molecules containing a 2,2-dimethyl-2H-chromene core.
O
OH
OH
OH
O
O
-H2O
+
R
R
R
R
H
1
Scheme 1. Simplified mechanism for observed transformations.
O
O
O
O
OH
HO
O
HO
O
OH
a
b
RO
O
O
+
I
OMOM
OMOM
OMOM
OMOM
22
21
7
23
R = CH3 (22Me),
CH2CH3 (22Et)
Scheme 2. Unsuccessful elimination. Reagents and conditions: (a) NaOH, ROH, reflux, 5 h; (b) DBU, toluene, 80 °C.
Interestingly, under the initial reaction conditions (column 4),
only compounds detected in the crude product mixtures. These
isolated products were all identified based on comparison to previ-
ously reported spectral data.17 The literature NMR data for chro-
mene 11 were not sufficiently diagnostic to state with certainty
which isomer was synthesized, and therefore an NOE experiment
was performed to unambiguously establish the structure of the
product. Specifically, irradiation of the benzylic methyl protons re-
sulted in significant enhancement of the signal of the single adja-
selective protection of the 4-hydroxy substituent of phloroace-
tophenone as either the tert-butyldimethylsilyl ether (4, Table 1,
entry 2) or the methoxymethyl ether (6, Table 1, entry 3) resulted
in a considerable drop in yield.
These findings, however, showed further promise for the regi-
oselectivity of this reaction, as none of the protected dichromeny-
lated products were observed. The structure of novel compound 5
was determined by full spectroscopic characterization, and 7 was
identified by comparison to previously published spectral data.19
In the case of the mono-protected phenol 6 (Table 1, entry 3,
column 4), the product was accompanied by significant levels of
octandrenolone (3) and also uncharacterized polymers, both
attributed to the breakdown of the mixed acetal-protecting group.
Decomposition was also seen in the reaction of the acetonide-con-
taining phenol 8 (Table 1, entry 4) under the standardized condi-
tions (column 4), although to a lesser degree; the structure of the
novel resulting chromene 9 was elucidated unambiguously by
X-ray crystallography.
Entries 4–10 presented the possibility for regioisomeric prod-
ucts. In nearly all cases, the chromene product indicated was the
only one observed in any significant amount.
The reactions using phenols 10, 12, and 14 (Table 1, entries 5–7)
display remarkable regioselectivity. While there are several prod-
ucts which could theoretically be produced in each case including
dichromenylated products and a number of regioisomeric mono-
chromenes, the shown products and starting materials were the
cent aryl proton. No such enhancement of the
a-vinyl hydrogen
was observed, a result consistent only with the indicated structure.
The difference in reactivity amongst phenols 10, 12, and 14
(Table 1, entries 5–7) illustrates the impact a single methyl
substitution can have on this method. A comparison of the relative
reactivity of phenols 14 (Table 1, entry 7) and 10 (Table 1, entry 5)
under the standard conditions (column 4) shows that incorpora-
tion of the C-6 methyl group resulted in a fivefold increase in yield.
Similarly, going from an aldehyde (14, Table 1, entry 7) to a methyl
ketone (12, Table 1, entry 6) also improved the yield. It is notewor-
thy that in both cases, the addition of the methyl group increases
the electron density in the aromatic ring.
When the carbonyl was located meta to the hydroxyl substitu-
ents as in compound 16 (Table 1, entry 8), only uncharacterized
polymer was observed after microwave irradiation. The formation
of this polymer apparently involves 3-methyl-2-butenal (1), as
irradiation of 16 without 1 provided full recovery of the starting
material. Notably, 4-hydroxybenzaldehyde proved to be impervi-
ous to this annulation method under a range of reaction conditions.

M. J. Adler, S. W. Baldwin / Tetrahedron Letters 50 (2009) 5075–5079
5077
Table 1
Yields for all investigated phenols under a set of standardized conditions, and highest yields (with conditions)a
Entry
Phenol
Chromene product
Standard:yieldb (%)
Best:time (h); equiv 1; yieldc (%)
O
O
HO
O
HO
OH
1
89
1; 3; 89
2
3
O
OH
O
O
HO
OH
HO
O
2
3
4
30
0.2; 1.5; 94d
0.5, 1.5; 29e
1; 1.5; 55d
4
5
OTBS
OTBS
O
O
O
HO
OH
HO
O
<5f,g
6
7
OMOM
OMOM
O
O
O
O
O
HO
HO
HO
HO
HO
16f,g
9
8
O
OH
O
O
O
H
O
H
HO
5
6
7
21
10
4
5; 3; 48
11
10
O
OH
O
HO
10; 3; 43
13
12
O
OH
H
O
H
HO
10; 3; 15
15
14
O
OH
O
H
8
9
None
0g
—
HO
OH
16
H3CO
O
O
H3CO
OH
7
1; 6; 63d
1; 6; 88d
17
19
18
20
OH
H3CO
H3CO
H3CO
H3CO
10
5
a
Reaction mixtures irradiated at 150 W in a 1 M solution in CDCl3 unless otherwise indicated. Crude product mixtures consisted of >95% product and starting materials
only unless otherwise indicated.
b
This column presents yields for all investigated phenols under a standard set of conditions. Reaction mixtures irradiated for 1 h with 3 equiv of 3-methyl-2-butenal (1).
This column presents our best yields for each substrate and the conditions used to achieve each particular yield.
Irradiated at 300 W.
0.25 M solution in CDCl3.
Crude reaction mixture contained significant amounts of undesired chromene side-products.
Crude product mixture contained significant amounts of uncharacterized compounds presumed to be polymeric material.
c
d
e
f
g

5078
M. J. Adler, S. W. Baldwin / Tetrahedron Letters 50 (2009) 5075–5079
Table 2
altering controllable experimental variables (time, power, equiva-
lents of 1, concentration) we were able to significantly improve
the yields relative to our initial conditions. The end results of this
pursuit (the best yields for each of the chromenes produced with
the conditions used) are also presented in Table 1 (column 5).
For example, this experimentation resulted in a drastic increase
in the production of novel chromene 5 (30–94%), and the natural
products precocenes I (18, 7–63%) and II (20, 5–88%). The reported
data were compiled from several trials; a discussion of illustrative
findings from these investigations accompanies the data shown in
Tables 2 and 3, which track the impact of changes in the controlla-
ble experimental variables.
In the series of 2,4-dihydroxycarbonylbenzenes (Table 2), posi-
tive effects were noted when either the power (entries 2, 6, and 10)
or the reaction time (entries 3, 7, and 11) was doubled from the
original standard conditions (entries 1, 5, and 9). When exposed
for yet longer reaction times (entries 4, 8, and 12), even higher
yields of the desired chromene products ensued, although these ef-
fects do not appear to be linear. In all trials, no significant amount
of any other products was observed.
Additional efforts were also put forth into the syntheses of the
natural products precocenes I (18) and II (20) utilizing this method
(Table 3). Doubling the power of the microwave irradiation (entries
2 and 7) from the standard conditions (entries 1 and 6) had a very
favorable effect on the production of the desired 2,2-dimethyl-2H-
chromenes, and when coupled with a doubling of the amount of 1
added (entries 3 and 8), yields were even further increased. Trials
at this elevated wattage run at twice the concentration (entries 4
and 9) displayed a minimal boost in the production of 18, but
the yield of 20 actually suffered due to decomposition of the mate-
rials. Increasing the time of exposure (entries 5 and 10) had a po-
sitive effect on the yield of both natural products.
While CDCl3 was chosen as the solvent for these reactions ini-
tially merely for facility of NMR evaluation, further studies were
performed to investigate the effect of solvent choice on this reac-
tion. While the use of CDCl3 as the solvent provided the maximum
yield for the conversion of this substrate to chromene product, no
clear trends regarding polarity or proticity emerged from this
investigation. The full results of these trials are reported in Table 4.
In an isolated trial in methanol using 6, arguably the least ame-
nable to this protocol of all the investigated phenols, chromene 7
Selected results from the optimization trials for the series of 2,4-dihydro-
xycarbonylbenzenesa
O
R
O
R
HO
R'
HO
R'
OH
O
Entry
Phenol
R
R0
Product
Power (W)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
10
10
10
12
12
12
12
14
14
14
14
H
H
H
H
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
H
11
11
11
11
13
13
13
13
15
15
15
15
150
300
150
150
150
300
150
150
150
300
150
150
1
1
2
5
1
1
2
10
1
1
21
26
25
48
10
16
21
43
4
H
H
H
H
H
H
H
10
11
12
H
H
H
9
7
15
2
10
a
Reaction mixtures contained 3 equiv of 1 in a 1 M solution in CDCl3.
Crude product mixtures consisted of >95% product and starting materials only
b
unless otherwise indicated.
Several non-carbonyl-containing phenols were also attempted
with varying degrees of success. Although no reaction was ob-
served with either phenol itself or with para-methoxyphenol un-
der several set of reaction conditions, both meta-methoxyphenol
(17, Table 1, entry 9) and 3,4-dimethoxyphenol (19, Table 1, en-
try 10) gave low yields of chromene products when exposed to
our initial reaction conditions (column 4). The low yields of pre-
cocenes I (18) and II (20) were subsequently improved dramati-
cally by altering some of the reaction variables (column 5).
These two materials were identified as the products of the reac-
tions of their respective parent phenols based on previously pub-
lished spectral data.22
Although it was not possible to establish a single set of micro-
wave reaction conditions that was optimal for all substrates, by
Table 3
Table 4
Selected results from the optimization trials for the synthesis of the natural products
Synthesis of octandrenolone in various solventsa
precocenes I (18) and II (20)a
O
O
H3CO
R
O
H3CO
OH
HO
OH
HO
O
R
OH
O
Entry Phenol
R
Product Time (h) Equiv 1 Concn (M) Yieldb (%)
1
2
3
4
5
6
7
8
9
17
17
17
17
17
19
19
19
19
19
H
H
H
H
H
18
18
18
18
18
1
1
1
1
2
1
1
1
1
2
3
3
6
3
3
3
3
6
3
3
1
1
1
2
1
1
1
1
2
1
7c
39
63
27d
53
5c
39
88
41
44
Entry
Solvent
e
Yieldb (%)
1
2
3
4
5
6
7
8
9
Hexane
Benzene
d-Chloroform
Tetrahydrofuran
Acetone
Ethanol
Methanol
Acetonitrile
N,N-Dimethylformamide
Water
2.0
2.3
4.8
7.5
21
24
33
37
38
80
na
11
24
60
9
17
22
34
5
OCH3 20
OCH3 20
OCH3 20
OCH3 20
OCH3 20
10
4
3
21
a
Reaction mixtures irradiated at 300 W unless otherwise indicated.
Crude product mixtures consisted of >95% product and starting materials only
10
11
b
None
unless otherwise indicated.
a
c
Reaction mixtures contained 3 equiv of 1 in a 1 M solution in CDCl3 and were
Reaction mixture irradiated at 150 W.
Crude product mixture contained significant amounts of uncharacterized
d
irradiated at 300 W for 1 h.
b
Yields were obtained by adding 1 equiv (based on starting phenol) of naph-
compounds presumed to be polymeric material.
thalene followed by GC–MS analysis.

M. J. Adler, S. W. Baldwin / Tetrahedron Letters 50 (2009) 5075–5079
5079
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reactions.
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chromene-containing compounds. By altering
a few of the
variables associated with this reaction, a variety of 2,2-dimethyl-
2H-chromenes have been successfully generated in good yield.
While optimization of the described method is ideal for its applica-
tion to novel substrates, the conditions are generally applicable to
a wide range of starting phenols. The results reported in this
publication provide the current state of this research; work on
improving the efficiency and generality of this method is ongoing.
Acknowledgments
The authors would like to thank undergraduates Ben Rothstein
and Scott Wilson for their experimental contributions to this work
and Dr. Chris Roy and Dr. Dewey McCafferty for generously allowing
the use of their synthesis microwaves. They also thank Dr. David
Pham of the X-ray Diffraction Lab of the Chemistry Department,
Duke University for his work in obtaining the crystal structure, Dr.
Tony Ribeiro of the DukeUniversity NMRCenter for help in acquiring
the NOE data, and Dr. George Dubay for assistance with GC–MS.
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Supplementary data
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Detailed experimental procedures, spectral data for all 2,2-di-
methyl-2H-chromene products, 1H and 13C spectra of the novel
structures 5 and 9, crystallographic data for chromene 9, and
NOE experiment spectra for the structural assignment of chromene
11. Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2009.06.090.
30. Appukkuttan, P.; Van der Eycken, E. Top. Curr. Chem. 2006, 266, 1–47.
31. For trials using the standardized conditions (150 W, 1 h, 3 equiv 1, 1 M
in CDCl3) the isolated yields are reported. For Tables
2 and 3, yields
were determined by NMR via comparison to an equimolar amount of
1,2-dimethoxyethane (based on starting phenol) added to the crude
reaction mixture after reaction completion and cooling. In all cases, the
References and notes
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