Thermal king closure reaction of 4-methyl-7-(1,1-disubstituted propyn-2-yloxy)chromen-2-ones: The effects of the substituents at propargylic position on reactivity and products

Article abstract of DOI:10.1081/SCC-200043203

The thermal ring closure of 4-methyl-7-(1,1-disubstituted propyn2-yloxy)chromen-2-ones (1) with gem-dihydro- or dimethyl-group at the propargylic position was carried out at high temperature such as refluxing in N,N-diethylaniline and resulted in the analogues of 4-methyl-2H-pyrano[6,5-h]2H- chromen-2-one (2). As the substituents at the propargylic position became bulkier, this ring closure could occur in much milder conditions such as refluxing in acetone or stirring in DMF at 80-90°C. The five-membered products, 4-methyl-furano [2,3-A]2H-chromen-2-ones (3) gradually became the main products.

Full text of DOI:10.1081/SCC-200043203

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Thermal Ring
Closure Reaction of
4‐Methyl‐7‐(1,1‐Disubstituted
Propyn‐2‐Yloxy)Chromen‐2‐Ones:
The Effects of the
Substituents at Propargylic
Position on Reactivity and
Products
Qian Zhang a , Ying Chen a , Yi Xia a , Zhengyu Yang
a & Peng Xia a
a Department of Medicinal Chemistry , School of
Pharmacy, Fudan University , Shanghai, 200032,
China
Published online: 12 Jan 2011.
To cite this article: Qian Zhang , Ying Chen , Yi Xia , Zhengyu Yang & Peng
Xia (2004) Thermal Ring Closure Reaction of 4‐Methyl‐7‐(1,1‐Disubstituted
Propyn‐2‐Yloxy)Chromen‐2‐Ones: The Effects of the Substituents at Propargylic
Position on Reactivity and Products, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:24, 4507-4515,
DOI: 10.1081/SCC-200043203
To link to this article: http://dx.doi.org/10.1081/SCC-200043203

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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4507–4515, 2004
Thermal Ring Closure Reaction of
4-Methyl-7-(1,1-Disubstituted Propyn-
2-Yloxy)Chromen-2-Ones: The Effects of
the Substituents at Propargylic Position
on Reactivity and Products
Qian Zhang, Ying Chen, Yi Xia, Zhengyu Yang,
*
and Peng Xia
Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai, China
ABSTRACT
The thermal ring closure of 4-methyl-7-(1,1-disubstituted propyn-
2-yloxy)chromen-2-ones (1) with gem-dihydro- or dimethyl-group at
the propargylic position was carried out at high temperature such as
refluxing in N,N-diethylaniline and resulted in the analogues of
4-methyl-2H-pyrano[6,5-h]2H-chromen-2-one (2). As the substituents
at the propargylic position became bulkier, this ring closure could
occur in much milder conditions such as refluxing in acetone or stirring
*
Correspondence: Peng Xia, Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai 200032, China; Fax: þ86-021-54237563; E-mail: pxia@
shmu.edu.cn.
4507
DOI: 10.1081/SCC-200043203
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4508
Zhang et al.
in DMF at 80–908C. The five-membered products, 4-methyl-furano
[2,3-h]2H-chromen-2-ones (3) gradually became the main products.
Key Words: Aryl propargylether; 4-methyl-7-(1,1-disubstituted propyn-
2-yloxy)chromen-2-ones; Thermal ring closure reaction.
2H-Pyrano[6,5-h]2H-chromen-2-one is an essential core moiety of many
potential bioactive compounds, such as the anti-HIV agents suksdorfin[1], ino-
phynone,[2] and calanolide[3], which possess a methyl- or gem-dimethyl-group
at the 8-position. The well-known synthetic route to them is via the thermal
ring closure reaction of aryl propargyl ether.[4–6] In our previous research
aimed at anti-HIV agents, we found that the substituents at the 8-position
might have considerable effects on the bioactivities.[7] This prompted us to
further synthesize the analogues of 2H-pyrano[6,5-h]2H-chromen-2-one
with different substituents at the 8-position via the thermal ring closure of
4-methyl-7-(1,1-disubstituted propyn-2-yloxy)chromen-2-ones. However,
the experimental results revealed that the substituents at the propargylic site
of the corresponding ethers (1) had a great effect on both the reactivity and
the ratio of two heterocyclic scaffolds, 4-methyl-2H-pyrano[6,5-h]2H-
chromen-2-one (2) and 4-methyl-furano[2,3-h]2H-chromen-2-one (3), in
products.
As Sch. 1 shows, the reaction of 4-methyl-7-hydroxy-2H-chromen-2-one
with propargylic bromide (a: R¼R0¼H) gave 4-methyl-7-(2-propynyloxy)2H-
chromen-2-one (1a), which was heated in N,N-diethylaniline to give the
normal six-membered ring closure product, 4-methyl-2H-pyrano[6,5-h]2H-
chromen-2-one (2a), exclusively. This result was similar to the reported
thermal reaction of 7-(1,1-dimethyl propyn-2-yloxy)chromen-2-one.[8]
To our surprise, besides the normal desired propargylic ether product, 7-(1-
methyl-1-ethyl-2-propynyloxy)-4-methyl-2H-chromen-2-one (1b), some further
ring closure products, 4,8-dimethyl-8-ethyl-2H-pyrano[6,5-h]2H-chromen-2-
one (2b) and 4-methyl-8-(10-methylpropyl)furano[2,3-h]2H-chromen-2-one
(3b) were isolated from the reaction of 4-methyl-7-hydroxy-2H-chromen-2-
one with 3-methyl-3-chloro-1-pentyne (b: R ¼ CH3, R0 ¼ C2H5) in the
presence of K2CO3 and KI by refluxing in acetone.
As the substituents at the propargylic position became more bulky,
3-methyl-3-chloro-1-hexyne (c: R ¼ CH3, R0 ¼ C3H7) and 3-ethyl-3-chloro-
1-pentyne (d: R ¼ R0 ¼ C2H5) reacted with 4-methyl-7-hydroxy-2H-
chromen-2-one to give a mixture of the corresponding ring closure products 2
and 3 exclusively, without the formation of the normal propargylic ethers 1.
The experiment reveals that the initial propargylic ether intermediates with
bulkier substituents at the propargylic position could undergo the ring closure
under the condition of refluxing in acetone or stirring in DMF at 80–908C.

Thermal Ring Closure Reaction
4509
Scheme 1. Reaction agents and conditions: 1) K2CO3 and KI in refluxing
acetone or in DMF at 80–908C; 2) refluxing in N,N-diethylaniline or refluxing in
acetone or stirring in DMF at 80–908C; 3) AD-mix-a in n-BuOH/H2O (1 : 1) at
0–48C.
In the previously reported method, this thermal ring closure occurred only
at higher temperature by refluxing in various solvents with a high boiling
point such as N,N-diethylaniline, N,N-dimethylaniline, diphenyl ether, etc.
(195–2208C).[4–6] The easy ring closure of 4-methyl-7-(1,1-bulky disubsti-
tuted propyn-2-yloxy)chromen-2-ones at a lower temperature might result
from their preferred conformations: the bulkier substituents at the propargylic
site force the ethynyl group close to the benzene moiety, thus leading to the
occurrence of the Claisen rearrangement at 8-position of 1 (as shown in Sch. 2).
Many efforts were unsuccessful to separate the six-membered ring
closure product (2) and the five-membered ring closure product (3) because

4510
Zhang et al.
Scheme 2.
of their similar physical properties. Finally, we separated them via
further dihydroxylation. The double bond in the pyran ring of 2H-
pyrano[6,5-h]2H-chromen-2-ones (2) reacted with AD-mix-a to give the
9R,10R-dihydroxy-compounds (4), but the double bond in the furan ring of
furano[2,3-h]2H-chromen-2-ones (3) did not react, and (3) remained in the
reaction mixture completely unchanged owing to their aromaticity. In
this step, the dihydroxylated compounds of 2H-pyrano[6,5-h]2H-
chromen-2-ones (4b–d) and unchanged furano[2,3-h]2H-chromen-2-ones
(3b–d) could be separated easily. Based on the yield of 4b–d and 3b–d,
the approximate ratio of 2 and 3 in the last ring closure reaction is listed in
Table 1.
Additionally, as shown in Table 1, the bulkiness of the substituents at
the propargylic position of 4-methyl-7-(1,1-disubstituted propyn-2-yloxy)
chromen-2-ones also affected the ratio of the six-membered and
five-membered ring closure products. It demonstrated that the substrates
with bulkier substituents were favored to form the five-membered products,
furano[2,3-h]2H-chromen-2-ones (3), due to the steric hindrance in the for-
mation of the six-membered ring (path a in Sch. 2).

Thermal Ring Closure Reaction
4511
Table 1. The approximate ratio of 2H-pyrano[6,5-h]2H-chromen-2-ones (2) and
furano[2,3-h]2H-chromen-2-ones (3) in ring closure reaction.
2H-Pyrano[6,5-h]2H-
chromen-2-ones (2) (%)
Furano[2,3-h]2H-
chromen-2-ones (3) (%)
a: R ¼ R0 ¼ H
100
80
0
20
45
85
b: R ¼ CH3, R0 ¼ C2H5
c: R ¼ CH3, R0 ¼ C3H7
d: R ¼ R0 ¼ C2H5
55
15
EXPERIMENTAL
General Synthesis for 1a–b
Excessive propargylic halide was added into a mixture of 4-methyl-7-
hydroxycoumarin (4.00 g, 22.70 mmol), K2CO3 (40 g, 0.29 mol), and KI
(3.77 g, 2.70 mmol) in 200 mL DMF. After stirring at 80–908C for 7–30 h,
the mixture was cooled and filtered. A white solid (1a–b) was obtained
after removal of the solvent and purified by flash column chromatography
(petroleum: CH3COOEt ¼ 10 : 1). In the preparation of 1b, an additional
mixture of 2b and 3b (0.37 g, 6.38%) was isolated from the reaction mixture.
7-(2-propargyloxy)-4-methyl-2H-chromen-2-one (1a). Yield: 94.65%; mp:
1
1408C (lit.[6], 1368C); H-NMR (CDCl3, 500 MHz) d: 2.42 (s, 3H, 4-CH3),
;;
2.58–2.59 (m, 1H, -C CH), 4.77–4.78 (m, 2H, -CH2), 6.17 (s, 1H, 3-H),
6.93–6.95 (m, 2H, 6 and 8-H), 7.53 (d, 1H, 5-H); MS m/z (%): 214 (Mþ, 67.89).
7-(1-methyl-1-ethyl-2-propynyloxy)-4-methyl-2H-chromen-2-one (1b).
1
Yield: 31.90%; mp: 110–1118C; H-NMR (CDCl3, 500 MHz d: 1.11 (t, 3H,
10-CH2CH3), 1.64 (s, 3H, 10-CH3), 1.90–2.04 (m, 2H, 10-CH2CH3), 2.40
;;
(s, 3H, 4-CH3), 2.67 (s, 1H, -C CH), 6.16 (s, 1H, 3-H), 7.06 (dd, J1 ¼ 8.8
Hz, J2 ¼ 2.2 Hz, 6-H), 7.32 (d, J ¼ 2.2 Hz, 8-H), 7.49 (d, 1H, J ¼ 8.8 Hz,
5-H); MS m/z (%): 256 (Mþ, 6.71), 241 (Mþ-CH3, 2.04), 227 (Mþ-C2H5,
8.38), 176 (100); Anal. Calcd. for C16H16O3: C, 74.98; H, 6.29; Found: C,
74.94; H, 6.47.
General Synthesis for 2a–b
1a–b (9.33 mmol) dissolved in 50 mL N,N-diethylaniline and refluxed
for 4–7 h. Then 250 mL 7% HCl was added and extracted with ethyl

4512
Zhang et al.
acetate (100 mL ꢀ 3). Organic layer was washed with water and brine, dried
with anhydrous Na2SO4, and filtered. After removal of the solvent, a white
solid (2a) was obtained by column chromatography (petroleum:
CH3COOEt ¼ 10 : 1). With 1b as substrate, the reaction gave the mixture of
2b and 3b. The recrystallization from petroleum/CH3COOEt (10 : 1) of this
mixture afforded pure 2b.
4-methyl-2H-pyrano[6,5-h]2H-chromen-2-one (2a). Yield: 49.00%; mp:
1
156–1588C, (lit.[6], 1568C); H-NMR (CDCl3, 300 MHz) d: 2.37 (s, 3H,
4-CH3), 4.92–4.93 (m, 2H, 8-H), 5.83–5.89 (tt, 1H, J ¼ 10.7 Hz, 9-H),
6.12 (s, 1H, 3-H), 6.72 (d, 1H, J ¼ 8.7 Hz, 6-H), 6.98 (d, 1H, J ¼ 10.7 Hz,
10-H), 7.33 (d, 1H, J ¼ 8.7 Hz, 5-H); MS m/z (%): 214 (Mþ, 99.69), 213
(Mþ-1, 100), 186 (Mþ-C¼O, 26.34), 185 (Mþ-1-C¼O, 66.94).
4,8-dimethyl-8-ethyl-2H-pyrano[6,5-h]2H-chromen-2-one (2b). Yield:
84.75%; mp: 80–818C; 1H-NMR (CDCl3, 300 MHz) d: 0.97 (t, 3H,
8-CH2CH3), 1.42 (s, 3H, 8-CH3), 1.69–1.79 (m, 2H, 8-CH2CH3), 2.37
(s, 3H, 4-CH3), 6.11 (s, 1H, 3-H), 5.65 (d, 1H, J ¼ 10.2 Hz, 9-H), 6.95
(d, 1H, J ¼ 10.2 Hz, 10-H), 6.73 (d, 1H, J ¼ 8.7 Hz, 6-H), 7.33 (d, 1H,
J ¼ 8.7 Hz, 5-H); MS m/z (%): 256 (Mþ, 3.97), 241 (Mþ-CH3, 11.12), 227
(Mþ-C2H5, 100); Anal. Calcd. for C16H16O3: C, 74.98; H, 6.29; Found: C,
74.79; H, 6.30.
General Synthesis for 3b–d and 4b–d
A crude excessive propargylic chloride from the reaction of correspond-
ing propargylic alcohol with thionyl chloride was added into a mixture of
4-methyl-7-hydroxycoumarin (4.00 g, 22.70 mmol), K2CO3 (40 g, 0.29 mol),
and KI (3.77 g, 2.70 mmol) in 200 mL DMF. After stirring for 24 h at 80–
908C, the mixture was cooled, filtered, and removed from the DMF via
vacuum distillation. A mixture of 2b–d and 3b–d was obtained with
column chromatography (petroleum: CH3COOEt ¼ 10 : 1), which was
directly used in the next reaction. The mixture of 2 and 3 in 50 mL
t-butanol/H2O (1 : 1) was added into a solution of K2OsO2(OH)4 (16.02 mg,
0.044 mmol), (DHQD)2-PHAL (34.28 mg, 0.044 mmol), K3Fe(CN)6 (2.22 g,
6.73 mmol), and K2CO3 (929 mg, 6.72 mmol) in 30 mL t-butanol/H2O
(1 : 1) and stirred at 0–48C for 96–240 h. Na2SO3 5 g was added and extracted
with ethyl acetate (50 mL ꢀ 4). Organic layer was washed with brine and
dried over anhydrous Na2SO4. Pure 3b–d and 4b–d were obtained in order
via column chromatography (petroleum: CH3COOEt ¼ 3 : 1).

Thermal Ring Closure Reaction
4513
4-methyl-8-(10-methylpropyl)furano[2,3-h]2H-chromen-2-one (3b). Yield:
11.68%; mp: 82–848C; 1H-NMR (CDCl3, 300 MHz) d: 0.94 (m, 3H,
-CH2CH3), 1.35 (d, 3H, J ¼ 6.8 Hz, 10-CH3), 1.65–1.70 and 1.80–1.85
(m ꢀ 2, 2H, -CH2CH3), 2.48 (s, 3H, 4-CH3), 2.89–2.93 (m, 1H, 10-H), 6.24
(s, 1H, 3-H), 6.75 (s, 1H, 9-H), 7.35 (d, 1H, J ¼ 8.7 Hz, 6-H), 7.43 (d, 1H,
J ¼ 8.7 Hz, 5-H); MS m/z (%): 256 (Mþ, 31.77), 241 (Mþ-CH3, 6.73), 227
(Mþ-C2H5, 100); Anal. Calcd. for C16H16O3: C, 74.98; H, 6.29; Found: C,
74.86; H, 6.30.
4-methyl-8-(10-methylbutyl)furano[2,3-h]2H-chromen-2-one (3c). Yield:
1
20.90%; mp: 84–868C; H-NMR (CDCl3, 500 MHz) d: 0.91–0.94 (t, 3H,
-CH2CH2CH3), 1.35 (d, 3H, J ¼ 6.8 Hz, 10-CH3), 1.25–1.79 (m ꢀ 4, 4H,
-CH2CH2CH3), 2.49 (s, 3H, 4-CH3), 2.97–3.01 (m, 1H, 10-H), 6.24 (s, 1H,
3-H), 6.73 (s, 1H, 9-H), 7.36 (d, 1H, J ¼ 8.7 Hz, 6-H), 7.43 (d, 1H,
J ¼ 8.7 Hz, 5-H); MS m/z (%): 270 (Mþ, 26.72), 255 (Mþ-CH3, 2.00), 241
(Mþ-C2H5, 7.85), 227 (Mþ-C3H7, 100); Anal. Calcd. for C17H18O3: C,
75.53; H, 6.71; Found: C, 75.40; H, 6.62.
4-methyl-8-(10-ethylpropyl)furano[2,3-h]2H-chromen-2-one (3d). Yield:
65.42%; mp: 80–828C; 1H-NMR (CDCl3, 300 MHz) d: 0.89 (t, 6H,
J ¼ 7.5 Hz, -CH2CH3 ꢀ 2), 1.75 (m, 4H, -CH2CH3 ꢀ 2), 2.48 (s, 3H,
4-CH3), 2.69 (m, 1H, J ¼ 7.0 Hz, 10-H), 6.24 (s, 1H, 3-H), 6.76 (s, 1H,
9-H), 7.36 (d, 1H, J ¼ 8.7 Hz, 6-H), 7.43 (d, 1H, J ¼ 8.7 Hz, 5-H); MS m/z
(%): 270 (Mþ, 34.73), 241 (Mþ-C2H5, 100); Anal. Calcd. for C17H18O3: C,
75.53; H, 6.71; Found: C, 75.44; H, 6.74.
(9R,10R)-9,10-dihydroxyl-8-ethyl-4,8-dimethyl-8,9,10-trihydro-2H-pyrano
1
[6,5-h]2H-cheomen-2-one (4b). Yield: 46.44%; mp: 172–1748C; H-NMR
(CDCl3, 500 MHz) d: 1.01 (t, 3H, 8-CH2CH3), 1.42 (s, 3H, 8-CH3), 1.70–
1.79 (m, 2H, 8-CH2CH3), 2.40 (s, 3H, 4-CH3), 3.23 (m, 1H, 9-OH), 4.00
(m, 1H, 10-OH), 3.95 (m, 1H, 9-H), 5.22 (m, 1H, 10-H), 6.13 (s, 1H, 3-H),
6.82 (d, 1H, J ¼ 8.8 Hz, 6-H), 7.46 (d, 1H, J ¼ 8.8 Hz, 5-H); MS m/z (%):
290 (Mþ, 15.12), 205 (100), 176 (Mþ-114, 18.67); Anal. Calcd. for
C16H18O5: C, 66.19; H, 6.25; Found: C, 66.07; H, 6.27.
(9R,10R)-9,10-dihydroxyl-8-propyl-4,8-dimethyl-8,9,10-trihydro-2H-pyrano
1
[6,5-h]2H-cheomen-2-one (4c). Yield: 28.16%; mp: 134–1368C; H-NMR
(CDCl3, 500 MHz) d: 0.94 (t, 3H, 8-CH2CH2CH3), 1.42 (s, 3H, 8-CH3),
1.44–1.90 (m ꢀ 3, 4H, 8-CH2CH2CH3), 2.40 (s, 3H, 4-CH3), 3.24–3.30
(m, 1H, 9-OH), 4.06–4.20 (m, 1H, 10-OH), 3.91–3.95 (m, 1H, 9-H),
5.19–5.23 (m, 1H, 10-H), 6.13 (s, 1H, 3-H), 681 (d, 1H, J ¼ 8.8 Hz, 6-H),
7.45 (d, 1H, J ¼ 8.8 Hz, 5-H); MS m/z (%): 304 (Mþ, 12.60), 205 (100),

4514
Zhang et al.
176 (Mþ-128, 14.23); Anal. Calcd. for C17H20O5: C, 67.09; H, 6.62; Found: C,
66.89; H, 6.67.
(9R,10R)-9,10-dihydroxyl-8,8-diethyl-4-methyl-8,9,10-trihydro-2H-pyrano
1
[6,5-h]2H-cheomen-2-one (4d). Yield: 10.68%; mp: 184–1868C; H-NMR
(CDCl3, 500 MHz) d: 0.93–0.97 (m, 6H, 8-CH2CH3 ꢀ 2), 1.62–1.68 and
1.94–2.02 (m ꢀ 2, 4H, 8-CH2CH3 ꢀ 2), 2.40 (s, 3H, 4-CH3), 3.12–3.13
(m, 1H, 9-OH), 4.15–4.16 (m, 1H, 10-OH), 4.06–4.08 (m, 1H, 9-H), 5.21–
5.22 (m, 1H, 10-H), 6.13 (s, 1H, 3-H), 684 (d, 1H, J ¼ 8.9 Hz, 6-H), 7.46
(d, 1H, J ¼ 8.9 Hz, 5-H); MS m/z (%): 304 (Mþ, 14.89), 205 (100), 176
(Mþ-128, 12.77); Anal. Calcd. for C17H20O5: C, 67.09; H, 6.62; Found: C,
66.85; H, 6.64.
ACKNOWLEDGMENT
This research was supported by a grant from National Science Foundation
of China (20272010 and 30200348) awarded to P. Xia and Y. Chen,
respectively.
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