Anti-AIDS agents 83. Efficient microwave-assisted one-pot preparation of angular 2,2-dimethyl-2H-chromone containing compounds

Article abstract of DOI:10.1016/j.tetlet.2010.06.058

A novel and efficient microwave-assisted one-pot reaction was developed to synthesize angular 2,2-dimethyl-2H-chromone-containing compounds, which is the first and key step in the synthesis of potent DCK and DCP anti-HIV agents. The newly developed microwave synthesis conditions dramatically shortened the reaction time from 2 days to 4 h with improved yields.

Full text of DOI:10.1016/j.tetlet.2010.06.058

Tetrahedron Letters 51 (2010) 4382–4386
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Tetrahedron Letters
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Anti-AIDS agents 83. Efficient microwave-assisted one-pot preparation of
angular 2,2-dimethyl-2H-chromone containing compounds
*
*
Ting Zhou, Qian Shi , Kuo Hsing Lee
Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 February 2010
Revised 4 June 2010
Accepted 12 June 2010
Available online 16 June 2010
A novel and efficient microwave-assisted one-pot reaction was developed to synthesize angular 2,2-
dimethyl-2H-chromone-containing compounds, which is the first and key step in the synthesis of potent
DCK and DCP anti-HIV agents. The newly developed microwave synthesis conditions dramatically short-
ened the reaction time from 2 days to 4 h with improved yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Microwave reaction
Angular 2,2-dimethyl-2H-chromone
One-pot reaction
Anti-HIV
1. Introduction
140 °C) to accomplish both alkylation and cyclization.5 However,
the maximum yield of the desired product still remained low
Suksdorfin (1), isolated from Lomatium suksdorfii, was discov-
ered in early 1994 to exhibit anti-HIV activity.1 Continuing research
led to the discovery of (30R, 40R)-(+)-cis-khellacone (DCK) analogs
and (30R, 40R)-di-O-(ꢀ)-camphanoyl-20,20-dimethyldihydropyr-
ano[2,3-f]chromone (DCP) analogs, some of which demonstrated
much more significant anti-HIV activity than 1.2–5 4-MDCK (2) and
2-EDCP (3) are potent representatives of these two series and were
selected as lead compounds for further modification to develop
more potent and selective anti-HIV agents as possible clinical trial
candidates. The skeletons of 1, 2, and 3 share a similar motif, a 2,2-
dimethyl-2H-chromene (rings B and C shown in Fig. 1). Because
the synthesis of the 2,2-dimethyl-2H-chromone motif is the first
and key step in the preparation of both DCK and DCP series, the
efficiency of this reaction dramatically affects the synthesis of the
desired final products.
In our prior studies, the C-ring was constructed by different
methods. For DCK compounds, a two-step reaction sequence in-
volved nucleophilic substitution with 3-chloro-3-methyl-1-butyne,
followed by Claisen rearrangement and cyclization in N,N-diethyl-
aniline at a reflux temperature over 200 °C.3 This transformation
generally needed over 48 h and the yield averaged below 40%. For
DCP analogs, a successful one-pot synthesis involved gradual addi-
tion of 4,4-dimethoxy-2-methyl-2-butanol into a refluxing solution
of 1-(2,4-dihydroxyphenyl)ethanone in pyridine (at approximately
(<40%) even with a 48-h reaction time. Both the conventional
syntheses of 2,2-dimethyl-2H-chromone were not time- or yield-
efficient, and partially attributable to the formation of a linear
by-product (b-series, such as 15b shown in Scheme 1). Therefore,
for scale-up synthesis of DCK and DCP compounds, a more efficient
synthetic approach was needed to shorten the reaction time,
increase the yield of the desired product (a-series), and for better
control of the formation of the linear by-product.
Microwave (MW) synthesis was considered to be a useful ap-
proach to accomplish these goals. One benefit of MW synthesis is
to manage the desired reaction under appropriate conditions (time,
temperature, and pressure) to achieve the desired product in a rea-
sonably high yield. In this Letter, we report herein our recent study
to design and conduct MW synthesis with varying reaction dura-
tion, temperature, and reagent, in order to optimize the synthesis
of angular 2,2-dimethyl-2H-chromenes (a-series), as the key and
desired intermediates in the synthesis of DCK and DCP analogs.
2. Results
In our previous Letter, the 2,2-dimethyl-2H-chromene 15a in
Scheme 1 was synthesized by the reaction of 1-(2,4-dihydroxy-
phenyl)ethanone with 4,4-dimethoxy-2-methyl-2-butanol in pyri-
dine. The best reported yield of 15a by this conventional method
was 38% with a reaction temperature of 140 °C and a reaction time
of 48 h. However, the by-product 15b was also obtained in 6.4%
yield under these conditions (Scheme 1). A possible mechanism
* Corresponding authors. Tel.: +1 919 843 6325; fax: +1 919 966 3893 (Q.S.); tel.:
+1 919 962 0066; fax: +1 919 966 3893 (K.H.L.).
E-mail addresses: qshi1@email.unc.edu (Q. Shi), khlee@unc.edu (K.H. Lee).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.058

T. Zhou et al. / Tetrahedron Letters 51 (2010) 4382–4386
4383
O
O
B
A
B
A
B
A
O
O
O
O
O
O
O
O
C
O
C
C
O
R =
O
OR
OR
O
OR
OR
O
O
2-EDCP (3)
4-MDCK (2)
Suksdorfin (1)
Figure 1. Structures of Suksdorfin (1), 4-MDCK (2) and 2-EDCP (3).
O
Table 1
Yields of 15a and 15b under varied microwave conditions
O
O
1
5
4
i
+
Temperature (°C)
Yield of 15a (%)
Yield of 15b (%)
2
O
OH
15a
HO
OH
O
OH
2 h
4 h
3.38
15.2
35.5
45.7
6 h
8 h
2 h 4 h
6 h
8 h
3
a
a
a
a
a
a
a
a
a
140
160
180
200
220
240
—
—
—
—
—
—
—
—
—
—
0.49
—
—
15b
4
a
23.1 23.8
41.5 41.9
49.3 54.0
54.0
35.8
1.40 2.33 2.47
4.11 5.02 7.76
6.06 6.27 7.14
7.32 8.05
5.92 5.60
a
Scheme 1. Synthesis of 15a,b. Reagents and conditions: (i) 4,4-dimethoxy-2-
methyl-2-butanol, pyridine, microwave condition.
a
a
a
52.7 57.4
—
—
6.4
—
—
a
a
a
a
—
38.0
—
a
is proposed in Scheme 2, which illustrates the formation of the de-
sired angular product 15a and the undesired by-product 15b. The
activated alkylating reagent, 4,4-dimethoxy-2-methyl-2-butanol,
initially attacks at the electron-rich position-3 or -5 of the starting
ethanone. Subsequently, cyclization occurs between the lone-pair
electrons of the ketone at position-4 and the electrophilic carbon
of the butene, and CH3OH is lost to form the angular (a-series from
position-3 attack) or linear (b-series from position-5 attack) prod-
uct. Using the same reagent, experiments were designed and con-
ducted using MW initiation to find better conditions to selectively
produce 15a. The results are listed in Table 1. The reaction temper-
ature was varied from 140 to 240 °C with 20 °C intervals, and the
reaction duration was extended from 2 to 8 h with 2-h intervals.
At a set reaction time, the yields of both 15a and 15b increased
at higher temperatures, but reached a maximum at 220 °C. At this
reaction temperature, the highest yield (57.4%) of the desired 15a
occurred at a reaction duration of 4 h. Although the yield of the
Reaction not performed.
Table 2
Yields of 21a and 21b under varied microwave conditions
Temperature (°C)
Yield of 21a (%)
Yield of 21b (%)
4 h 6 h
4 h
6 h
180
200
220
240
38.4
49.7
55.7
52.6
44.8
2.94
3.62
4.08
4.58
2.14
a
a
—
—
—
—
a
a
a
a
—
—
a
Reaction not performed.
undesired 15b also increased slightly (6.40% vs 7.32%) under these
conditions (220 °C/4 h), the MW synthesis was still a significant
improvement compared with the best reported conventional reac-
tion conditions (57.4% vs 38% yield of 15a, respectively).
N
OCH3
OH
OH-
H
H
O
N
HO
OMe
OCH3
OCH3
N
O
O
5
HN
CH3OH
3
HO
OH
O
OH
O
OH
4
H
a
b
OCH3
N
OCH3
Attack on 3-position
15a
15b
O
H3CO
O
H
HN
CH3OH
O
OH
O
OH
Attack on 5-position
Scheme 2. Possible mechanism for observed transformations.

4384
T. Zhou et al. / Tetrahedron Letters 51 (2010) 4382–4386
Table 3
Application of optimized microwave conditions (220 °C, 4 h) with diverse starting materials9,10
Entry
Starting material
Angular product a
Linear product b
Yield of a
Yield of b
O
O
O
1
57.4
7.32
HO
HO
OH
O
O
O
OH
O
O
OH
O
4
5
15b
16b
15a
16a
2
3
4
66.4
72.6
63.5
9.54
N/A
2.65
OH
O
O
O
OH
O
OH
O
HO
HO
OH
O
OH
O
O
O
OH
O
6
17b
17a
OH
O
OH
O
O
OH
O
7
18b
18a
5
6
40.3
31.6
N/A
HO
HO
O
O
O
O
O
O
8
19b
19a
O
O
O
O
O
O
O
O
O
O
O
9
5.47
20b
20a
7
8
55.7
38.9
4.08
27.2
O
HO
O
O
O
10
21b
21a
OH
OH
O
O
OH
O
O
O
O
OH
O
O
O
O
HO
HO
O
O
O
11
22b
22a
O
OH
OH
9
42.6
38.1
17.4
7.05
O
O
12
23b
23a
OH
O
OH
O
OH
O
10
HO
O
O
O
O
O
13
24b
24a

T. Zhou et al. / Tetrahedron Letters 51 (2010) 4382–4386
4385
Table 3 (continued)
Entry
Starting material
Angular product a
Linear product b
Yield of a
Yield of b
OH
O
OH
O
OH
O
N
11
36.2
4.33
HO
N
O
O
N
25b
25a
14
To verify the optimized MW conditions, a second series of reac-
tions were conducted using 3-hydroxy-9H-xanthane-9-one (10) as
the starting material to make the corresponding tetracyclic prod-
uct (21a). The reaction temperatures, times, and yields are listed
in Table 2. The best yield (55.7%) of the desired product 21a was
again reached at 220 °C for 4 h, and was about 10 times better than
the yield obtained from the conventional method with the same
alkylating reagent (4.34%, Table 4, entry 7), suggesting that
220 °C/4 h may be widely applicable to efficiently produce differ-
ent dimethylchromene-related products including 8,8-dimethyl-
8H-pyrano[2,3-f]chromenes, 3,3-dimethyl-pyrano[2,3-c]xanthen-
7(3H)-ones, or other compounds, such as 3,3,12-trimethyl-3H-pyr-
ano[2,3-c]acridin-7(12H)-one.
Next, different substances containing a phenolic ring were re-
acted with 4,4-dimethoxy-2-methyl-2-butanol under the opti-
mized MW conditions. The results are listed in Table 3. Most
reactions generated two new products, the desired angular a-prod-
uct and an undesired linear b-product, plus differing amounts of
the recovered starting materials. The exceptions were entries 3
and 5 (Table 3), in which only the desired a-products were ob-
served by TLC and MS. In all cases, the desired angular a-products
were formed predominantly compared with the undesired linear
b-products, implying that the MW reaction conditions are efficient
and applicable to the synthesis of diverse dimethylchromene-re-
lated products. The a- and b-products could be separated by silica
gel chromatography and identified by NMR spectroscopy.
undesired product 15b, leading to a much higher ratio of desired/
undesired product. Both bi- (8, 9) or tri-cyclic (10–14) compounds
(Table 3, entries 5–10) were also treated with 4,4-dimethoxy-2-
methyl-2-butanol under the established MW reaction conditions.
The yields of the desired a-products were generally lower (31.6–
55.7%, Table 3, entries 5–11) relative to those obtained with single
ring reactants (57.4–72.6%, Table 3, entries 1–4). However, they
were much higher than those obtained with conventional reaction
conditions utilizing the same alkylating reagent. For example, the
yields of the desired products 19a, 20a, and 21a were only 13.5%,
23.9%, and 4.34%, respectively, with conventional synthesis but
40.3%, 31.6%, and 55.7% with MW synthesis (Table 4). Unexpect-
edly, 19b was not detected under either set of reaction conditions;
however, the yields of 19a were not comparably high, and the
starting material 8 was mainly recovered. Compound 22a was pre-
pared previously by the reaction of 1,3-dihydroxy-xanthen-9-one
(11) with 2-chloro-2-methylbutyne. After a two-step reaction se-
quence, the desired product was obtained in a low yield of 12.5%
(Table 4).6 Under the MW conditions, the yield of 22a increased
to 38.9%. A substantial quantity of 22b by-product was also ob-
tained (27.2%), suggesting that the meta-hydroxy group may play
a role in assisting the formation of the linear b-type compound.
Compounds 12 and 13 with a methyl substituent at the 6- or 7-po-
sition yielded lower amounts of b-products (23b and 24b) relative
to 22b, although the yields of the desired a-products (23a and 24a)
were not significantly changed compared with 22a. Compound 25a
was synthesized previously from 2-methyl-3-butyn-2-ol through
either two- or multiple-step reactions, in a total yield of less than
20% (Table 4).7,8 Under the optimized MW conditions, we success-
fully synthesized 25a from 3-hydroxy-10-methylacridin-9(10H)-
one (14) in an improved yield of 36.2%.
Adding a methyl or ethyl group at the 6-position of 1-(2,4-dihy-
droxyphenyl)ethanone (Table 3, entries 1–3) generated better
yields of the desired products [57.4% 15a (6-H), 66.4% 16a (6-
CH3), 72.6% 17a (6-CH2CH3)]. Although the yield of the undesired
16b was slightly higher than that of 15b, interestingly, the unde-
sired 17b was not detected under the applied reaction conditions.
With approximately 25% of the starting material 6 recovered, this
3. Discussion and conclusions
result suggested
a stereo-favorable cyclization toward the
3-position. With 1-(2,4-dihydroxyphenyl)propan-1-one (7) as the
starting material (Table 3, entry 4), the desired 18a was obtained
in 63.5% yield, which was 6% higher than the yield of 15a from
1-(2,4-dihydroxyphenyl)ethanone (4) (Table 3, entry 1). In addi-
tion, the undesired 18b was obtained in 5% lower yield than the
In this research, we were able to successfully utilize a micro-
wave initiation method to synthesize the desired angular 2,2-di-
methyl-2H-chromenes that are the key intermediates in the
syntheses of anti-HIV DCP and DCK analogs. Through alkylation
and cyclization between an appropriate starting compound and
Table 4
Comparisons of conventional and microwave syntheses
Entry no. in Table 3/Products
Conventional heating system (140 °C/48 h for entries 1, 5–7)a (%)
MW condition (220 °C/4 h)a (%)
Angular product a Linear product b
Angular product a
Linear product b
1/15
5/19
6/20
38.0
13.6
23.9
4.34
12.5
20
6.40
N/A
57.4
40.3
31.6
55.7
38.9
36.2
7.32
N/A
5.47
4.08
27.2
4.33
2.55
1.20
6.30
7/21
8/226,b
14/257,c
d
—
a
b
c
Alkylating reagent: 2,2-dimethoxy-2-methyl-2-butanol.
Alkylating reagent: 2-chloro-2-methylbutyne, two-step reaction.
Alkylating reagent: 2-methyl-3-butyn-2-ol, two-step reaction.
Not available in the reference.
d

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T. Zhou et al. / Tetrahedron Letters 51 (2010) 4382–4386
alkylating reagent, a series of the desired 2,2-dimethyl-2H-chro-
mene products, including 8,8-dimethyl-8H-pyrano[2,3-f]chrom-
enes, 3,3-dimethyl-pyrano[2,3-c]xanthen-7(3H)-ones, and other
products, such as 3,3,12-trimethyl-3H-pyrano[2,3-c]acidin-
7(12H)-one, were obtained in a one-pot reaction. Compared to
the literature-reported methods, the newly developed micro-
wave-assisted conditions dramatically shortened the reaction time
from 2 days to 4 h with much higher to comparable yields. Increas-
ing the reaction temperature from 140 to 220 °C and extending the
reaction time favored the formation of both a- and b-products;
however, with a lower fold increase in the undesired b-product.
Although the yields of the desired products are still not ideal, the
current optimized MW conditions significantly improve selective
synthesis of the desired products in comparison to the literature
reports with conventional heating conditions.
We also analyzed the factors that might affect yield and regiose-
lectivity in this reaction. The reaction yield and the regioselectivity
were influenced by electronic effects on the phenolic ring. Elec-
tron-donating groups, such as alkyl groups at the 6-postion of 1-
(2,4-dihydroxyphenyl)ethanone, should increase the electron den-
sity at the 3-position, which consequently enhanced alkylation
reactivity at this position and the relative percentage of the desired
a-product. In contrast, a lone electron-pair on a hydroxy group
introduced at the 1-position of xanthenone (Table 3, entries 8-
10) results in higher electron density at the 2-position and, there-
fore, reduced the regioselectivity between a- and b-products. In
addition, steric effects of ring substituents may also play a role in
the alkylation and cyclization. Introducing an ethyl group at the
6-postion (6, Table 3, entry 3) blocked alkylation from occurring
at the 5-position, which led exclusively to the desired product 17a.
This study demonstrates a significant advancement because
this MW method, under optimized conditions, can be widely uti-
lized with diverse ring systems, including phenone, chromenone,
xanthenone, and acridinone. Therefore, this synthetic methodology
dramatically broadens the possibility of efficiently exploring struc-
turally diverse DCK and DCP analogs as novel anti-HIV agents. This
work is currently ongoing in the authors’ laboratories, and the re-
sults will be reported shortly.
Acknowledgment
This investigation was supported by the Grant AI 33066 from
the National Institute of Allergy and Infectious Disease (NIAID)
awarded to K.H.L.
References and notes
1. Lee, T.; Kashiwada, Y.; Huang, L.; Snider, J.; Cosentino, M.; Lee, K. H. Bioorg. Med.
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3. Xie, L.; Takeuchi, Y.; Cosentino, L. M.; Lee, K. H. J. Med. Chem. 1999, 42, 2662.
4. Yu, D. L.; Brossi, A.; Kilgore, N.; Wild, C.; Allaway, G.; Lee, K. H. Bioorg. Med.
Chem. Lett. 2003, 13, 1575.
5. Yu, D. L.; Chen, C. H.; Brossi, A.; Lee, K. H. J. Med. Chem. 2004, 47, 4072.
6. Schneider, J.; Evans, E. L.; Grunberg, E.; Fryer, R. I. J. Med. Chem. 1972, 15, 266.
7. Motiur Rahman, A. F.; Liang, J. L.; Lee, S. H.; Son, J. K.; Jung, M. J.; Kwon, Y.;
Jahng, Y. Arch. Pharm. Res. 2008, 31, 1087.
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9. Sample procedure for microwave-assisted synthesis of 2,2-dimethyl-2H-
Chromones. Synthesis of 16a and 16b (Table 3, entry 2): 20,40-Dihydroxy-60-
methyl-acetophenone (5) (200.0 mg, 1.20 mmol), 4,4-dimethoxy-2-methyl-2-
butanol (0.37 mL, 2.40 mmoL), and anhydrous pyridine (2 mL) were added into
2–5 mL microwave vial and sealed. After pre-stirring for 20 s, the reaction
temperature was increased to 220 °C for 4 h under high microwave absorption
condition. At completion, the reaction mixture was cooled to room
temperature, diluted with EtOAc and washed separately with aqueous HCl
(10%) and brine. The organic layer was collected and the solvent was removed
under vacuum. The residue was purified by column chromatography (hexanes/
EtOAc = 97:3) to afford 16a in 66.4% yield and 16b in 9.54% yield. Compound
16a: MS (ESI+) m/z (%) 233 (M++1, 100); 1H NMR (CDCl3, 300 MHz) d (ppm) 6.69
(1H, d, J = 9.9 Hz, H-4), 6.19 (1H, s, H-8), 5.52 (1H, d, J = 9.9 Hz, H-3), 3.31 (3H, s,
COCH3-6), 2.53 (3H, s, CH3-7), 1.43 (6H, s, CH3-2,2). Compound 16b: MS (ESI+)
m/z (%) 233 (M++1, 100); 1H NMR (CDCl3, 300 MHz) d (ppm) 6.52 (1H, d,
J = 10.2 Hz, H-4), 6.27 (1H, s, H-8), 5.65 (1H, d, J = 10.2 Hz, H-3), 2.60 (3H, s,
COCH3-6), 2.49 (3H, s, CH3-5), 1.42 (6H, s, CH3-2,2).
10. Microwave initiator utilized to synthesize 2H-chromones (15–25) is Biotage
initiator (300 W).