Condition-controlled selective synthesis of coumarins and flavones from 3-(2-hydroxyphenyl)propiolates and iodine

Article abstract of DOI:10.1016/j.tetlet.2011.05.150

2H-Chromen-2-ones (coumarins) and 4H-chromen-4-ones (flavones) were selectively prepared via the reaction of 3-(2-hydroxyphenyl)propiolates with iodine in toluene and N,N-dimethylformide, respectively.

Full text of DOI:10.1016/j.tetlet.2011.05.150

Tetrahedron Letters 52 (2011) 4164–4167
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Tetrahedron Letters
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Condition-controlled selective synthesis of coumarins and flavones
from 3-(2-hydroxyphenyl)propiolates and iodine
⇑
⇑
Shuying Cai, Yang Shen, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
2H-Chromen-2-ones (coumarins) and 4H-chromen-4-ones (flavones) were selectively prepared via the
reaction of 3-(2-hydroxyphenyl)propiolates with iodine in toluene and N,N-dimethylformide, respectively.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 May 2011
Accepted 31 May 2011
Available online 12 June 2011
Both 2H-chromen-2-ones (coumarins) and 4H-chromen-4-ones
adjacent to triple bond.12 When iodine was used as Lewis acid to
activate the triple bond, the hydroxyl group could nucleophili-
1
13
(
flavones) are of paramount importance because of their bioactiv-
2
ities in nature. Coumarins are widely used in the pharmaceutical
company as precursors in the synthesis of a variety of anticoagu-
lant pharmaceuticals and some even more efficient rodenticides
that work by the same anticoagulant mechanism. Coumarins also
cally attack the electron-deficient triple bond intramolecularly. A
fused product could thus be constructed. However, when 1a re-
acted with iodine in acetonitrile, 3,4-diiodo-2H-chromen-2-one
(2a) was obtained instead of obtaining the expected benzofuran.
In order to have the optimized reaction condition, we altered the
ratio of iodine to substrate, the solvent, and the reaction tempera-
ture, individually (Table 1). Increasing molar ratio of iodine to 1a
would benefit the reaction (Table 1, entries 1–3). N,N-Dimethyl-
acetamide (DMAc) worked for the reaction (Table 1, entry 4). How-
ever, when the mixture of 1a and iodine was refluxed in
dichloromethane (DCM), only trace amount of 2a was detected
by TLC after 36 h (Table 1, entry 5). When the reaction mixture
was refluxed in commercial toluene for 28 h, 2a was isolated in a
yield of 42% (Table 1, entry 6). To our delight, the yield was dra-
matically increased to 92% when the fresh-distilled toluene was
3
possess clinical values in the treatment of lymphedema. Industry
of flavones has grown enormously due to its acknowledged effects
against atherosclerosis, osteoporosis, diabetes mellitus, and certain
4
cancers. Both structures contain benzopyrone, but in different
connection as shown below. General synthetic methods leading
to coumarin skeleton include the well-known Perkin reaction be-
5
tween salicylaldehyde and acetic anhydride, Pechmann condensa-
6
7
tion, and others. Synthetic ways leading to the flavone skeleton
8
are the Allan–Robinson reaction where o-hydroxyaryl ketones
9
react with aromatic anhydrides, the Auwers synthesis, the Al-
gar–Flynn–Oyamada reaction10 where a chalcone undergoes an
oxidative cyclization and others.11 In this Letter, we would like to
report an iodine-mediated annulation of methyl 3-(2-hydroxy-
phenyl)propiolates, which furnishes coumarin or flavone skeleton
with high selectivity under different reaction conditions.
Table 1
Formation of coumarin skeleton from 1a and iodine under various reaction conditions
I
COOCH3
O
I
O
I2
solvent
O
O
O
OH
O
2
H-chromen-2-one
4H-chromen-4-one
2a
1a
coumarin
flavone
Entry
Solvent
T (°C)
I
2
(equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
CH
CH
CH
DMAc
DCM
3
3
3
CN
CN
CN
82
82
82
110
40
1
1.5
2
2
2
72
48
48
48
36
28
12
74
64
82
43
Trace
42
92
In order to construct a fused heterocyclic structure, such as ben-
zofuran, we selected methyl 3-(2-hydroxy-phenyl)propiolate (1a)
as substrate because the hydroxyl group of this substrate is
Toluene
110
90
2
2
Tolueneb
a
⇑
Corresponding authors. Tel./fax: +86 571 87951512.
E-mail addresses: pinglu@zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
Isolated yield.
Fresh-distilled toluene.
b
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.150

S. Cai et al. / Tetrahedron Letters 52 (2011) 4164–4167
4165
Table 2
COOR2
I
Formation of flavone 3a from 1a and iodine under various reaction conditions
R1
R1
I
I2
COOCH3
O
toluene
0 C, 12 h
O
O
COOCH3
OH
I2
o
9
1
2
2b
1
1
1
1
1
b R = CH , R = CH3
c R = Cl, R = CH3
R = CH
3
, 62 %
solvent
3
1
2
2c
2a
2a
1
1
1
o
O
3a
R
R
R
= Cl, 60 %
= H, 68 %
= H, 48 %
OH
110 C
1
2
d R = H, R = i-Pr
1a
e R = H, R2 = C H
1
2
5
Yielda (%)
Entry
Solvent
I
2
(equiv)
Time (h)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
0
72
72
72
72
72
72
48
72
ND
13
48
54
54
66
42
25
Scheme 1. Synthesis of coumarin skeleton.
0.25
0.5
1
1.2
1.5
2
used as the solvent (Table 1, entry 7). Under the optimized reaction
conditions, substrates (1b–d) afforded the corresponding products
14
in yields between 48% and 68% (Scheme 1).
DMF
Dimethylformamide (DMF) has been widely used as formyla-
tion reagent for many years. The typical example is the Vilsmeier
reaction where the combination of DMF and phosphoryl trichloride
Tolueneb
1.5
a
Isolated yield.
2 equiv DMF relative to 1a was used.
b
1
5
is used. Later on, lots of combinations were developed, such as
1
6
the mixture of DMF, thionyl chloride and alkaline iodide, the
mixture of DMF and phosphine–halogen complexes 7, and the
mixture of DMF and iodine pentafluoride.18 When the reaction of
1
1
a and iodine was performed in DMF, an interesting product was
obtained. Instead of obtaining 2a, methyl 4-oxo-4H-chromene-3-
carboxylate (3a) was constructed efficiently. As we can see from
Table 2, the most suitable ratio of iodine to 1a was found to be
CO R2
2
I
O
2
R1
R1
2
DMF
10 C
2 h
CO R
2
o
1
7
1
.5:1 (Table 2, entries 1–7). Due to the fact that DMF was not only
OH
O
used as a polar solvent but also did participate in the reaction, we
tested this reaction in toluene, but with a 2:1 ratio of DMF to 1a
1
2
3b R1 = CH , R = CH , 61 %
2
1
1
1
1
1
b R = CH , R = CH3
c R = Cl, R = CH3
d R = H, R = i-Pr
3
3
3
1
2
3c R1 = Cl, R = CH , 76 %
2
3
(Table 2, entry 8). The yield significantly decreased to 25% even
1
2
1
2
3d R = H, R = i-Pr, 43 %
3e R = H, R = C H , 67 %
3f R = H, R = Ph, 50 %
though the reaction was refluxed and lasted for 72 h. Substrates
with methyl (1b) and chloro (1c) afforded the corresponding prod-
ucts (3b and 3c) in yields of 61% and 76%, respectively, while the
ester with different alcohol parts (1d, 1e, and 1f) did not affect
the reaction. Thus, 3d, 3e, and 3f were prepared smoothly (Scheme
1
2
1
2
e R = H, R = C H
2
5
2 5
f R = H, R2 = Ph
1
1
2
Scheme 2. Synthesis of flavones 3 from 1.
1
9
2
). Structures of 3 were analyzed by spectroscopy and further
20
confirmed by X-ray analysis of 3c (Fig. 1).
According to the reference method, the final step for the prepa-
ration of the starting material (1) was the deprotection of
methoxymethyl (MOM) of the corresponding phenols. However,
deprotection of 4a and 4b failed to get the desired products. Con-
sidering the nucleophilicity of the lone pair electrons of the pheno-
lic oxygen of these MOM-protected compounds,21 we directly
reacted 4a and 4b with iodine in DMF, respectively. To our sur-
prise, compounds with flavone skeleton (3g and 3h) could also
be constructed in yields of 89% and 81%, respectively (Scheme
2
2
3
). However, any effort on the transformation of MOMs of 1a–
1
f to 3a–3f failed although the starting material (1a–1f) disap-
Figure 1. X-ray diffraction of 3c.
peared based on TLC tracking.
At the beginning, we believed that the triple bond was hydrated
first to form b-ketoester as a key intermediate for formylation by
DMF and sequential cyclization. Therefore, we used methyl 3-(2-
hydroxyphenyl)-3-oxopropanoate (5) as substrate to run the
reaction under the same condition. However, instead of getting
the desired product with flavone skeleton, iodation on the acti-
vated methylene and the sequentially intramolecular esterification
occurred. 3,3-Diiodochroman-2,4-dione (6) was obtained in high
yield. In order to test the necessity of the adjacent hydroxy group
and the ester group in the substrate, ethyl 3-phenylpropiolate (7)
and 2-(phenylethynyl)phenol (8) were used as substrates to react
with iodine in DMF, individually. Both reactions did not occur
based on TLC tracking. In the presence of n-butanol, 7 did not react
with iodine in DMF as well, which implied that the intermolecular
reaction did not happen. When dimethylacetamide (DMAc) was
used as solvent instead of DMF, 2a was isolated (Table 1, entry
CO CH3
O
O
O
2
I
2
O
O
DMF
O
O
10 oC, 72 h
1
4
a
3g, 89 %
2
CO CH3
I2
O
O
DMF
1
10 oC, 72 h
O
O
O
4b
3h, 81 %
Scheme 3. Synthesis of flavone 3 skeleton from 4.
4
). DMAc did not participate in the reaction while DMF did.

4
166
S. Cai et al. / Tetrahedron Letters 52 (2011) 4164–4167
O
O
I
I
CO Me
2
I
CO Me
OMe
NMe
2
CO Me
2
I2
O
−H
O
-I
N
OH
OH
B
OH
N
O
2
H
1
a
A
C
O
O
I
I
O
O
OMe
O
O
I
CO Me
2
CO
2
Me
−
I
2
O
NMe2
NMe2
−HNMe
2
D
E
3a
H
Scheme 4. Possible mechanism for the formation of flavone.
References and notes
O
O
O
I
1.
(a) Harborne, J. B.; Baxter, H. In The Handbook of Natural Flavonoids; John Wiley
Son: Chichester, UK, 1999; Vols. 1 and 2,; (b) Harborne, J B. The Flavonoids:
OEt
I
&
Advances in Research since 1986; Chapman and Hall: London, UK, 1994.
(a) Lewis, K.; Stermitz, F. R.; Collins, F. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 1433;
O
6
O
OH
2.
5
(
b) Costantino, L.; Rastelli, G.; Gamberini, M. C.; Vinson, J. A.; Bose, P.; Iannone,
A.; Staffieri, M.; Antolini, L.; Corso, A. D.; Mura, U.; Albasini, A. J. Med. Chem.
999, 42, 1881; (c) Huang, Y. T.; Blagg, B. S. J. J. Org. Chem. 2007, 72, 3609.
1
CO Et
2
3. (a) Farinola, N.; Piller, N. Lymphat. Res. Biol. 2005, 3, 81; (b) Casley-Smith, J. R.;
Morgan, R. G.; Piller, N. B. New Engl. J. Med. 1993, 329, 1158.
4
5
.
.
Cermak, R. Expert Opin. Drug Met. 2008, 4, 17.
Saha, N. N.; Desai, V. N.; Dhavale, D. D. J. Org. Chem. 1999, 64, 1715.
OH
6. Woodruff, E. H. Org. Synth. 1944, 24, 69.
7
.
(a) Crosby, D. G.; Berthold, R. V. J. Org. Chem. 1962, 27, 3083; (b) Harvey, R. G.;
Cortez, C.; Ananthanarayan, T. P.; Schmolka, S. J. Org. Chem. 1988, 53, 3936; (c)
Yonezawa, N.; Nonoyama, S.; Saigo, K.; Hasegawa, M. J. Org. Chem. 1985, 50,
7
8
3026.
8
.
.
(a) Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192; (b) Dyke, S. F.; Ollis, W.
D.; Sainsbury, M. J. Org. Chem. 1961, 26, 2453; (c) Wheller, T. S. Org. Synth. 1952,
Based on these results, we postulated a possible mechanism for
3
2, 72.
this transformation (Scheme 4). Activated by iodine, the triple
bond became electron-deficient as described in the previous re-
9
(a) Auwers, K. V. Ber. 1908, 41, 4233; (b) Auwers, K. V. Ber. 1915, 48, 85; (c)
Auwers, K. V. Ber. 1916, 49, 809.
2
3
port. Both oxygen and nitrogen in DMF are electron-rich due to
its resonance nature. By nucleophilic attack from oxygen of DMF
on the iodonium intermediate (A), iminium intermediate (B) was
afforded, which could be intramolecularly attacked by the ortho
hydroxy group. Via electron push-pull effect, the fused ring (C)
was opened and a new iminium intermediate (D) was formed
which further cyclized to E. Subsequent exclusion of iodine and
dimethylamine led to the formation of flavone skeleton (3a)
successfully.
10. Gormley, T. R.; O’Sullivan, W. I. Tetrahedron 1973, 29, 369.
1
1. (a) Awuah, E.; Capretta, A. Org. Lett. 2009, 11, 3210; (b) Ma, W.; Li, X.; Yang, J.;
Liu, Z.; Chen, B.; Pan, X. Synthesis 2006, 2489; (c) Liang, B.; Huang, M.; You, Z.;
Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097; (d)
Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765.
12. Yang, Q.; Alper, H. J. Org. Chem. 2010, 75, 948.
13. (a) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075;
b) Harkat, H.; Blanc, A.; Weibel, J. M.; Pale, P. J. Org. Chem. 2008, 73, 1620.
(
1
4. Typical procedure for the synthesis of 2a: Iodine (2 mmol) was added to the
solution of methyl 3-(2-hydroxyphenyl)propiolate 1a (1 mmol) in fresh-
distilled toluene (10 mL). The mixture was stirred at 90 °C for 12 h. The
resulting reaction solution was quenched with saturated Na
20 mL) and extracted with 3 Â 10 mL of ethyl acetate. The extract was dried
over anhydrous Na SO and evaporated in vacuo. The residue was purified by
silica gel column chromatography with hexane–EtOAc. Compound 2a: yellow
2 2 3
S O solution
In this Letter, we reported the selective reaction between 3-
2-hydroxyphenyl)propiolate and iodine in toluene and DMF,
(
(
2
4
respectively. The reaction of 3-(2-hydroxyphenyl)propiolate and
iodine in toluene afforded coumarins, while the reaction of 3-(2-
hydroxyphenyl)propiolate and iodine in dimethylforamide gave
flavones. Assisted by iodine, DMF participated in the reaction,
implying that the combination of DMF and iodine might be an effi-
cient formylating reagent in both laboratory and industry.
1
solid, mp 187–190 °C; H NMR (400 MHz, CDCl
7
3
) d 7.62–7.52 (m, 2H), 7.39–
) d 158.2, 151.4, 133.0, 132.5,
127.5, 125.1, 120.7, 120.1, 117.0 ppm; HRMS (ESI) calcd for
13
.32 (m, 2H) ppm; C NMR (100 MHz, CDCl
3
9 4 2 2
C H O I
+
(
[M+Na] ), 420.8205; found, 420.8193.
1
5. (a) Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119; (b) Meth-Cohn, O.; Stanforth, S. P.
Compd. Org. Synth. 1991, 2, 777; (c) Campaigne, E.; Archer, W. L. Org. Synth. Coll.
1963, 4, 331; (d) Campaigne, E.; Archer, W. L. Org. Synth. Coll. 1953, 33, 27.
6. Femández, I.; Begoña, B.; Muñoz, S.; Pedro, J. R.; de la Salud, R. Synlett 1993,
1
4
89.
Acknowledgment
17. Caputo, R.; Ferriri, C.; Palumbo, G. Synth. Commun. 1987, 17, 1629.
8. Stevens, T. E. Chem. Ind. 1958, 1090.
1
1
9. Typical procedure for the synthesis of 3a: Iodine (1.5 mmol) was added to the
solution of methyl 3-(2-hydroxyphenyl)propiolate 1a (1 mmol) in DMF
(10 mL). The mixture was stirred at 110 °C for 72 h. The resulting reaction
We thank the National Natural Science Foundation of China
Nos. 21032005, 20872128) for the financial support of this
research.
(
solution was quenched with saturated Na
2
S
2
O
3
solution (25 mL) and extracted
SO
4
with 3 Â 10 mL of ethyl acetate. The extract was dried over anhydrous Na
2
and evaporated in vacuo. The residue was purified by silica gel column
1
Supplementary data
chromatography with hexane–EtOAc. 3a: White solid, mp 79–82 °C, H NMR
(
7
400 MHz, CDCl
3
) d 8.70 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H),
13
.49 (dd, J = 16.4, 8.1 Hz, 2H), 3.94 (s, 3H) ppm; C NMR (101 MHz, CDCl
3
)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.150.
1
73.4, 164.1, 162.1, 155.6, 134.2, 126.6, 126.3, 125.14, 118.1, 116.1, 52.4 ppm.
+
HRMS (ESI) calcd for C11H O ([M+Na] ), 227.0315; found, 227.0312.
8
4

S. Cai et al. / Tetrahedron Letters 52 (2011) 4164–4167
4167
2
0. CCDC: 790082 contains the supplementary crystallographic data for
compounds 3c. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data _reques t@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
126 °C; 1H NMR (400 MHz, CDCl
3
) d 10.03 (d, J = 8.7 Hz, 1H), 8.67 (s, 1H), 8.12
(d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.64 (t,
J = 7.4 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H) ppm; 13C NMR (101 MHz,
6
DMSO-d ) 175.3, 164.1, 159.2, 156.8, 136.2, 131.0, 130.4, 129.6, 128.3, 127.3,
+
127.1, 118.6, 118.5, 117.0, 52.5 ppm. HRMS (ESI) calcd for C15
10 4
H O ([M+Na] ),
2
2
1. Okitsu, T.; Nakazawa, D.; Kobayashi, A.; Mizohata, M.; In, Y.; Ishida, T.; Wada,
A. Synlett 2010, 203.
2. Synthesis of 3g: Iodine (1.5 mmol) was added to the solution of 4a (1 mmol) in
DMF (10 mL). The mixture was stirred at 110 °C for 72 h. The resulting reaction
277.0471; found, 277.0468.
23. (a) Ji, K. G.; Zhu, H. T.; Yang, F.; Shu, X. Z.; Zhao, S. C.; Liu, X. Y.; Shaukat, A.;
Liang, Y. M. Chem. Eur. J. 2010, 16, 6151; (b) He, Z. H.; Li, H. R.; Li, Z. P. J. Org.
Chem. 2010, 75, 4636; (c) Xie, Y. X.; Yan, Z. Y.; Qian, B.; Deng, W. Y.; Wang, D. Z.;
Wu, L. Y.; Liu, X. Y.; Liang, Y. M. Chem. Commun. 2009, 5451; (d) Xie, Y. X.; Liu,
X. Y.; Wu, L. Y.; Han, Y.; Zhao, L. B.; Fan, M. J.; Liang, Y. M. Eur. J. Org. Chem.
2008, 1013; (e) de Souza, A. V. A.; Mendonça, G. F.; Bernini, R. B.; de Mattos, M.
C. S.; Braz, J. Chem. Soc. 2007, 18, 1575.
solution was quenched with saturated Na
2
S
2
O
3
solution (25 mL) and extracted
SO
with 3 Â 10 mL of ethyl acetate. The extract was dried over anhydrous Na
2
4
and evaporated in vacuo. The residue was purified by silica gel column
chromatography with hexane–EtOAc. Compound 3g: yellow solid, mp 122–