Total synthesis of six 3,4-unsubstituted coumarins

Article abstract of DOI:10.3390/molecules181215613

In this article we describe a new methodology for the total synthesis of 3,4-unsubstituted coumarins from commercially available starting materials. Six examples were prepared, including five naturally occurring coumarins-7-hydroxy- 6,8-dimethoxycoumarin (isofraxidin), 7-hydroxy-6-methoxycoumarin (scopoletin), 6,7,8-trimethoxycoumarin, 6,7-dimethoxycoumarin (scoparone), and 7,8-dihydroxycoumarin (daphnetin) and one synthetic coumarin, 7-hydroxy-6-ethoxycoumarin. Moreover, five important o-hydroxybenzaldehyde intermediates were also obtained, namely 2,4-dihydroxy-3,5- dimethoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 5-ethoxy-2,4- dihydroxybenzaldehyde, 2-hydroxy-3,4,5-trimethoxybenzaldehyde, and 2-hydroxy-4,5-dimethoxybenzaldehyde. The method developed herein involves just three or four steps and allows for the rapid synthesis of these important molecules in excellent yields. This is the first synthesis of 6,7,8-trimethoxycoumarin and 7-hydroxy-6-ethoxycoumarin.

Full text of DOI:10.3390/molecules181215613

Molecules 2013, 18, 15613-15623; doi:10.3390/molecules181215613
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Total Synthesis of Six 3,4-Unsubstituted Coumarins
Wenqing Gao 1, Qingyong Li 1,2,*, Jian Chen 1, Zhichao Wang 1 and Changlong Hua 1
1
Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University,
Harbin 150040, China; E-Mails: gaowenqing1314@126.com (W.G.);
18042486759@189.com (J.C.); wzc870715@163.com (Z.W.); ghe521@163.com (C.H.)
2
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
* Author to whom correspondence should be addressed; E-Mails: liqy@zjut.edu.cn or
li_qingyong@126.com; Tel.: +86-571-8832-0984.
Received: 28 October 2013; in revised form: 8 December 2013 / Accepted: 10 December 2013 /
Published: 13 December 2013
Abstract: In this article we describe a new methodology for the total synthesis of
3,4-unsubstituted coumarins from commercially available starting materials. Six examples
were prepared, including five naturally occurring coumarins—7-hydroxy-6,8-dimethoxy-
coumarin (isofraxidin), 7-hydroxy-6-methoxycoumarin (scopoletin), 6,7,8-trimethoxy-
coumarin, 6,7-dimethoxycoumarin (scoparone), and 7,8-dihydroxycoumarin (daphnetin)
and one synthetic coumarin, 7-hydroxy-6-ethoxycoumarin. Moreover, five important
o-hydroxybenzaldehyde intermediates were also obtained, namely 2,4-dihydroxy-3,5-
dimethoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 5-ethoxy-2,4-dihydroxy-
benzaldehyde, 2-hydroxy-3,4,5-trimethoxybenzaldehyde, and 2-hydroxy-4,5-dimethoxy-
benzaldehyde. The method developed herein involves just three or four steps and allows
for the rapid synthesis of these important molecules in excellent yields. This is the first
synthesis of 6,7,8-trimethoxycoumarin and 7-hydroxy-6-ethoxycoumarin.
Keywords:
3,4-unsubstituted
coumarins;
o-hydroxybenzaldehyde
derivatives;
6,7,8-trimethoxycoumarin; 7-hydroxy-6-ethoxycoumarin
1. Introduction
Coumarins (2H-1-chromene-2-ones) are abundant in Nature and are common motifs found in drugs,
dyes, spices, and agricultural chemicals. In particular, 3,4-unsubstituted coumarins are the most

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common naturally occurring coumarins, which show potential antimalarial [1], antioxidant [2–6],
antimicrobial [7], anti-inflammatory [8], and antitumor [9–11] activity, however, their abundance in
plants is very low and the purification processes are complex. Therefore, various methods have been
developed for the total synthesis of coumarins [11–22], including the Perkin [23], Pechmann [24],
and Knoevenagel reactions [25]. These reactions mostly lead to coumarins with substituents at the
3- or 4-position. A one-pot Wittig reaction/cyclization has been adopted by de Kimpe for the synthesis
of 3,4-unsubstituted coumarins [26]. Herein, we report the highly efficient total synthesis of five
naturally occurring coumarins, as well as a synthetic 3,4-unsubstituted coumarin (Figure 1). To the
best of our knowledge, this is the first report on the total synthesis of coumarins 3 and 4.
Figure 1. The structure of the synthesized coumarins.
2. Results and Discussion
Coumarins 1, 2, and 3 were synthesized from simple starting materials (Scheme 1).
The hydroxyl group was protected using pivaloyl chloride [27] to give the corresponding products in
100% yield. These compounds were then iodinated in 80%, 77%, 80% yields, respectively, using
N-iodo-succinimide [28,29], followed by hydrolysis using cuprous oxide, pyridine-2-aldoxime,
tetrabutylammonium bromide, and cesium hydroxide [30]. The resulting o-hydroxybenzaldehydes
were finally reacted with ethyl (triphenylphosphoranylidene) acetate in N,N-diethylaniline, forming
coumarins 1, 2, and 3 as described above [26].

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Scheme 1. Syntheses of coumarins 1, 2, and 3.
Reagents and conditions: (a) (CH3)3COCl, DMAP, Et3N, CH2Cl2; (b) 10 NIS, CF3COOH, CH3CN, reflux;
11,12 N-iodosuccinimide (NIS), CF3SO3H, MeOH; (c) CsOH, syn-2-pyridinealdoxime, Cu2O, Bu4NBr, N2,
H2O; (d) (C6H5)3P=CHCOOCH2CH3, Et2NPh, N2, reflux.
It was envisaged that this method could be applied to the synthesis of 6,7-dimethoxy-8-
hydroxycoumarin (34) and 5,6,7,8-tetrahydroxycoumarin (35) (Scheme 2).
Scheme 2. Attempted syntheses of coumarins 34, 35.
Reagents and conditions: (a) 26 (CH3)3COCl, DMAP, Et3N, CH2Cl2; 27 MeSO4, K2CO3, CH3CN; (b) 28 NIS,
CF3COOH, CH3CN, reflux; 29 NIS, CF3SO3H, MeOH; (c) CsOH, syn-2-pyridinealdoxime, Cu2O, Bu4NBr,
N2, H2O.

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Protection of the hydroxyl groups using pivaloyl chloride and iodination of the resulting compounds
proceeded as expected, but hydrolysis of the iodo-compounds 30 and 31 failed to afford the desired
products 32 and 33. It was presumed that both electronic effects and steric hindrance of the
three methoxy groups and the hydroxyl group at the ortho position of 30 and 31 affected the success of
these reactions.
Synthesis of coumarins 4 and 5 (Scheme 3) began with the iodination of 3,4,5-
trimethoxybenzaldehyde (19) and veratraldehyde (20), respectively, both in 99% yield. Hydrolysis of
2-iodo-3,4,5-trimethoxybenzaldehyde (21) and 2-iodo-4,5-dimethoxybenzaldehyde (22) afforded
2-hydroxy-3,4,5-trimethoxybenzaldehyde (23) and 2-hydroxy-4,5-dimethoxybenzaldehyde (24) in
83% and 85% yield, respectively. Finally, the o-hydroxybenzaldehydes 23 and 24 were converted to
the corresponding coumarins 4 and 5. The overall yield of 4 and 5 was higher compared to that of
compounds 1–3.
Scheme 3. Syntheses of coumarins 4 and 5.
Reagents and conditions: (a) 19 NIS, CF3COOH, CH3CN, reflux; 20 NIS, CF3SO3H, MeOH; (b) CsOH,
syn-2-pyridinealdoxime, Cu2O, Bu4NBr, N2, H2O; (c) (C6H5)3P=CHCOOCH2CH3, Et2NPh, N2, reflux.
Finally, daphnetin (6) was synthesized using the one-pot Wittig/cyclization reaction from
commercially available 2,3,4-trihydroxybenzaldhyde in 65% yield (Scheme 4).
Scheme 4. Synthetic procedures of coumarin 6.
Reagents and conditions: (a) (C6H5)3P=CHCOOCH2CH3, Et2NPh, N2, reflux.

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This result for daphnetin (6) was identical compared to the previously reported synthesis [26].
Similarly for scopoletin (2), the overall yield of 50.4% (for four steps) is comparable to that of the
previously reported synthesis (52.8%) [24]. However, for isofraxidin (1) and scoparone (5), the yields
of 57.6% and 77.4% are significantly higher compared to those obtained previously [23,25]. The key
step in this novel method is the hydrolysis of the iodinated compound, as substituents on the phenyl
group have a great influence on this reaction. Activating groups can reduce the probability of
hydrolysis and steric hindrance at the ortho position also influences the reaction.
3. Experimental
All solvents and commercially available reagents were purchased from the suppliers and used
1
13
without further purification. H-NMR and C-NMR spectra were recorded using Bruker DPX 500
(Bruker, Billerica, MA, USA) and 300 spectrometers, respectively. Spectra were recorded in CDCl3
and DMSO solutions and chemical shifts are reported in parts per million (ppm) relative to
tetramethylsilane (TMS) as the standard. IR spectra were recorded on an Infinity Spectrum One
spectrophotometer (Shimadzu, Kyoto, Japan). Mass spectra (Applied Biosystems, Toronto, Canada)
were recorded on an Agilent 1100 Series VS (ES, 4000 V) mass spectrometer. Melting points were
measured using a Büchi B-450 apparatus (Shanghaishenguang, Shanghai, China). Flash chromatography
was performed with ACROS silica gel (particle size 0.030–0.040 mm, pore diameter ca. 6 nm) using a
glass column.
3.1. General Procedure for the Synthesis of Coumarins 1–6
The appropriate o-hydroxybenzaldehyde (1 mmol) and ethyl(triphenylphosphoranylidene) acetate
(1.2 mmol) were dissolved in N,N-diethylaniline (1.5 mL) and the resulting mixture was stirred under a
N2 atmosphere and reflux for 15 min. The solvent was removed under reduced pressure (1 mmHg,
52 °C) and the resulting brown oil was purified by column chromatography (petroleum ether-ethyl
acetate, 3:1).
7-Hydroxy-6,8-dimethoxy-2H-chromen-2-one (Isofraxidin, 1). Yellow solid. Yield: 80%. mp (°C):
147–148.5 (lit. 148–149) [13]. 1H-NMR (500 MHz, CDCl3): 3.95 (s, 3H, OCH3), 4.10 (s, 3H, OCH3),
6.16 (s, 1H, Ar), 6.29 (d, J = 9.5 Hz, 1H, 3-CH), 6.66 (s, 1H, OH), 7.60 (d, J = 9.5 Hz, 1H, 4-CH);
13C-NMR (75 MHz, CDCl3) 56.6 (OCH3), 61.2 (OCH3), 105.0 (C-5), 110.7 (C-4a), 112.5 (C-3),
135.2 (C-8), 143.5 (C-7), 144.5 (C-8a), 145.3 (C-4), 146.1 (C-6), 160.6 (C-2); IR (KBr, cm−1)
1699 (C=O), 1570 (C=C), 3327 (br, OH); HRMS (EI): m/z 223 [M+H+].
7-Hydroxy-6-methoxy-2H-chromen-2-one (Scopoletin, 2). Yellow solid. Yield: 85%. mp (°C):
202.7–204.4 (lit. 204) [15]. 1H-NMR (500 MHz, CDCl3): 3.82 (s, 3H, OCH3), 6.23 (d, J = 9.5 Hz, 1H,
3-CH), 6.79 (s, 1H, Ar), 7.23 (s, 1H, Ar), 7.92 (d, J = 9.5 Hz, 1H, 4-CH), 10.33 (s, 1H, OH); 13C-NMR
(75 MHz, CDCl3) 56.4 (OCH3), 103.2 (C-8), 110.0 (C-5), 111.0 (C-3), 112.1 (C-4a), 144.9 (C-4),
145.7 (C-6), 150.0 (C-7), 151.6 (C-8a), 161.1 (C-2); IR (KBr, cm−1) 1558 (C=C), 1683 (C=O),
3334 (br, OH). HRMS (EI): m/z 193 [M+H+].

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7-Hydroxy-6-ethoxy-2H-chromen-2-one (3). Yellow solid. Yield: 80%. mp (°C): 138.5–142.0.
1H-NMR (500 MHz, CDCl3): 1.37 (t, J = 7.0 Hz, 3H, CH3), 4.06 (q, J = 7.0 Hz, 2H, OCH2-),
6.23 (d, J 9.5 Hz, 1H, 3-CH), 6.81 (s, 1H, Ar), 7.90 (d, J = 9.5 Hz, 1H, 4-CH), 10.27 (s, 1H, CHO);
13C-NMR (75 MHz, CDCl3) 15.1 (CH3), 64.8 (-CH2O-), 103.2 (C-8), 111.0 (C-5), 111.2 (C-3),
112.1 (C-4a), 144.8 (C-4), 144.9 (C-6), 149.9 (C-7), 151.9 (C-8a), 161.1 (C-2); IR (KBr, cm−1)
1558 (C=C), 1699 (C=O), 1716, 3383 (br, OH);.HRMS (EI): m/z 207 [M+H+].
6,7,8-Trimethoxy-2H-chromen-2-one (Dimethylfraxetin, 4). Yellow solid. Yield: 81%. mp (°C):
1
103.8–104.5 (lit. 104–105) [31]. H-NMR (500 MHz, CDCl3): 3.91 (s, 3H, OCH3), 4.00 (s, 3H,
OCH3), 4.04 (s, 3H, OCH3), 6.35 (d, J = 9.5 Hz,1H, 3-CH), 6.69 (s, 1H, Ar), 7.63 (d, J = 9.5 Hz, 1H,
4-CH); 13C-NMR (75 MHz, CDCl3) 56.3 (OCH3), 61.5 (OCH3), 61.8 (OCH3), 103.7 (C-5),
114.3 (C-4a), 115.2 (C-8), 141.2 (C-6), 143.1 (C-7), 143.5 (C-4), 145.9 (C-8), 150.1 (C-8a),
160.5 (C-2); IR (KBr, cm−1) 1566 (C=C), 1716 (C=O). HRMS (EI): m/z 237 [M+H+].
6,7-Dimethoxy-2H-chromen-2-one (Scoparone, 5). Yellow solid. Yield: 91%. mp (°C): 142.6–148.4
1
(lit. 145–146) [18]. H-NMR (500 MHz, CDCl3): 3.81 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
6.30 (d, J = 9.5 Hz, 1H, 3-CH), 7.07 (s, 1H, Ar), 7.25 (s, 1H, Ar), 7.955 (d, J = 9.5 Hz, 1H, 4-CH);
13C-NMR (75 MHz, CDCl3) 56.3 (OCH3), 56.6 (OCH3), 100.5 (C-8) 109.3 (C-5), 111.6 (C-4a),
113.1 (C-3), 144.8 (C-6), 146.3 (C-4), 149.9 (C-8a), 153.0 (C-7), 161.0 (C-2); IR (KBr, cm−1)
1516 (C=C), 1558, 1708 (C=O), 1616, 3566 (br, OH). HRMS (EI): m/z 207 [M+H+].
7,8-Dihydroxy-2H-chromen-2-one (Daphnetin, 6). Yellow solid. Yield: 65%. mp (°C): 265.7–267.2
1
(lit. 265−268) [21]. H-NMR (500 MHz, CDCl3): 6.20 (d, J = 6.5 Hz, 1H, 3-CH), 6.81 (s, 1H, Ar),
7.03 (s, 1H, Ar), 7.91 (d, J = 7.0 Hz, 1H, 4-CH), 9.79 (d, J = 7.0 Hz, 1H, OH), 9.80 (d, J =7.0Hz, 1H,
13
OH); C-NMR (75 MHz, CDCl3) 111.7 (C-3), 112.5 (C-4a), 112.9 (C-6), 119.3 (C-5), 132.6 (C-8),
144.2 (C-8a), 145.6 (C-4), 150.1 (C-7), 160.9 (C-2); IR (KBr, cm−1) 1674 (C=O), 1508 (C=C), 1589.
HRMS (EI): m/z 179 [M+H+].
3.2. General Procedure for the Synthesis of Compounds 10–12
The corresponding phenol (3 mmol) was dissolved in dichloromethane (5 mL) and
4-dimethylamiopyridine (0.1 mmol) was added. The reaction was stirred for 0.5 h before addition of
pivaloyl chloride (6 mmol) followed by dropwise addition of triethylamine (6 mmol). The reaction
mixture was stirred at room temperature for 2 h. The reaction solution was poured into
dichloromethane (100 mL) and washed with saturated sodium chloride solution (2 × 100 mL) and
saturated sodium bicarbonate solution (2 × 100 mL). The organic phase was collected, dried over
anhydrous magnesium sulfate, and filtered, and then the solvent was removed in vacuo to obtain
compounds 10–12.
4-Formyl-2,6-dimethoxyphenyl-2,2-dimethylpropanoate (10, C14H18O5). Yellow solid. Yield 100%.
1
mp (°C): 108–110.9. H-NMR (CDCl3, 500 MHz): 1.39 (s, 9H, C(CH3)3), 3.88 (s, 6H, OCH3),
7.14 (s, 2H, Ar), 9.91 (s, 1H, CHO); 13C-NMR (75 MHz, CDCl3) 27.2 (CH3), 29.7 (CH3),

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39.2 (CC=O), 56.37 (2 × OCH3), 106.2 (C-3,5) 134.1 (C-1), 134.4 (C-4), 153.0 (C-2,6), 175.8 (C=O),
191.2 (CHO); IR (KBr, cm−1) 1751 (C=O), 1691, 1608; MS (EI): m/z 267 [M+H+].
4-Formyl-2-methoxyphenyl-2,2-dimethylpropanoate (11, C13H16O4). White solid. Yield: 100%.
1
mp (°C): 83.8–95.0. H-NMR (500 MHz, CDCl3): 1.38 (s, 9H, C(CH3)), 3.88 (s, 3H, OCH3),
7.19 (d, J = 7.5Hz, 1H, Ar), 7.46 (s, 1H, Ar), 7.48 (d, J = 7.5 Hz, 1H, Ar), 9.95 (s, 1H, CHO);
13C-NMR (75 MHz, CDCl3) 27.2 (3 × CH3), 39.2(CC=O), 56.1 (OCH3), 110.8 (C-2), 123.4 (C-6),
124.8 (C-5), 135.1 (C-1), 145.6 (C-4), 152.1 (C-3), 176.1 (-COO-), 191.2 (CHO); IR (KBr, cm−1)
1689 (C=O), 1749. MS (EI): m/z 237 [M+H+].
2-Ethoxy-4-formylphenyl-2,2-dimethylpropanoate (12, C14H18O4). White solid. Yield: 100%. mp (°C):
1
83.8–85.3. H-NMR (500 MHz, CDCl3): 1.38 (s, 9H, C(CH3)3), 1.41 (d, J = 7.0 Hz, 3H, CH3),
4.10 (t, J = 7.0 Hz, 2H, OCH2-), 7.19 (d, J = 8.5 Hz, 1H, Ar), 7.46 (s, 1H, Ar), 7.46 (d, J = 7.0 Hz, 1H, Ar),
9.93 (s, 1H, CHO); 13C-NMR (75 MHz, CDCl3) 14.6 (CH3), 27.2 (CH3), 39.2 (CC=O), 64.5 (-OCH2-),
111.4 (C-2), 123.3 (C-6), 124.6 (C-5), 135.0 (C-1), 145.6 (C-4), 151.4 (C-3), 176.0 (C=O),
191.2 (CHO); IR (KBr, cm−1) 1699 (C=O), 1602; MS (EI): m/z 251 [M+H+].
3.3. General Procedure for the Synthesis of 13, 21, 22.
The appropriate benzaldehyde (3 mmol) was dissolved in acetonitrile (5 mL) and N-iodosuccinimide
(6 mmol) was added. Trifluoroacetic acid (0.3 μmol) was then added dropwise and the reaction
mixture was heated under reflux for 6 h. After cooling to room temperature, the reaction solution was
quenched by the addition of sodium sulfite (3 mmol) and stirred for five minutes. Subsequently,
CH2Cl2 (100 mL) was added and the solution was extracted with saturated sodium chloride solution
(3 × 100 mL). The organic phase was collected, dried over anhydrous magnesium sulfate, and filtered,
and the solvent was removed in vacuo. Column chromatography (petroleum ether-ethyl acetate, 40:1)
afforded the corresponding iodinated compound.
4-Formyl-3-iodo-2,6-dimethoxyphenyl-2,2-dimethylpropanoate (13, C14H17O5). Yellow solid. Yield: 80%.
1
mp (°C): 100.7–102.5. H-NMR (500 MHz, CDCl3): 1.40 (s, 9H, C(CH3)3), 3.86 (s, 3H, OCH3),
13
3.85 (s, 3H, OCH3), 7.37 (s, 1H, Ar), 10.08 (s, 1H, CHO); C-NMR (75 MHz, CDCl3) 27.1 (CH3),
39.3 (CC=O), 56.5 (OCH3), 61.5 (OCH3), 90.3 (C-2), 108.6 (C-6), 133.0 (C-4), 139.0 (C-1),
153.0 (C-5), 152.3 (C-3), 175.3 (C=O), 191.0 (C=O), 195.2 (C=O); IR (KBr, cm−1) 1691 (C=O), 1759;
MS (EI): m/z 393 [M+H+].
2-Iodo-3,4,5-trimethoxybenzaldehyde (21, C10H11O3). Yellow solid. Yield: 99%. mp (°C): 67.6–68.1.
1H-NMR (500 MHz, CDCl3): 3.97 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
13
7.35 (s, 1H, OCH3), 10.05 (s, 1H, CHO); C-NMR (75 MHz, CDCl3) 61.2 (OCH3), 61.0 (OCH3),
56.3 (OCH3), 91.6 (C-2), 108.6 (C-6), 130.6 (C-1), 147.8 (C-4), 153.0 (C-5), 154.1 (C-3),
195.3 (CHO); IR (KBr, cm−1) 1687 (C=O); MS (EI): m/z 323 [M+H+].
2-Iodo-4,5-dimethoxybenzaldehyde (22, C9H9O2). Yellow solid. Yield: 99%. mp (°C):: 145.1–145.5.
1H-NMR (500 MHz, CDCl3): 3.92 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 7.31 (s, 1H, Ar), 7.42 (s, 1H, Ar),
13
9.87 (s, 1H, Ar); C-NMR (75 MHz, CDCl3) 56.1 (OCH3), 56.5 (OCH3), 92.8 (C-4), 111.1 (C-5),

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121.8 (C-1), 128.4 (C-6), 149.8 (C-3), 154.5 (C-2), 194.9 (CHO); IR (KBr, cm−1) 1672 (C=O);
MS (EI): m/z 293 [M+H+].
3.4. General Procedure for the Synthesis of 14 and 15
The appropriate benzaldehyde (3 mmol) was dissolved in methanol (20 mL) and N-iodosuccinimide
(6 mmol) was added. Trifluoromethanesulfonic acid (6 mmol) was then added dropwise and the reaction
mixture was stirred at room temperature for 6 h. The reaction was quenched by the addition of sodium
sulfite and the reaction mixture was stirred for five minutes. Subsequently, dichloromethane (100 mL)
was added and the solution was extracted with saturated sodium chloride solution (3 × 100 mL). The
organic phase was collected, dried over anhydrous magnesium sulfate, and filtered; then, the solvent
was removed in vacuo. Column chromatography (petroleum ether-ethyl acetate, 40:1) afforded the
corresponding iodinated compound.
4-Formyl-5-iodo-2-methoxyphenyl-2,2-dimethylpropanoate (14, C13H15O4). Yellow solid. Yield: 77%.
1
mp (°C): 98.4. H-NMR (500 MHz, CDCl3): 1.36 (s, 9H, C(CH3)3), 3.86 (s, 3H, OCH3), 7.50 (s, 1H,
13
Ar), 7.58 (s, 1H, Ar), 9.96 (s, 1H, CHO); C-NMR (75 MHz, CDCl3) 27.1 (3 × CH3), 39.2 (CC=O),
56.2 (OCH3), 89.6 (C-2), 112.7 (C-6), 133.2 (C-3), 134.1 (C-1), 145.7 (C-4), 152.3 (C-5),
175.7 (-COO-), 194.9 (CHO); IR (KBr, cm−1) 1693 (C=O), 1751; MS (EI): m/z 363 [M+H+].
2-Ethoxy-4-formyl-5-iodophenyl-2,2-dimethylpropanoate (15, C14H17O4). Yellow solid. Yield: 80%.
1
mp (°C): 81.7–83.8. H-NMR (500 MHz, CDCl3): 1.37 (s, 9H, C(CH3)3), 1.39 (t, J = 7.0 Hz, 3H,
-CH3), 4.08 (q, J = 7.0 Hz, 2H, OCH2-), 7.47 (s, 1H, Ar), 7.58 (s, 1H, Ar), 9.95 (s, 1H, CHO);
13C-NMR (75 MHz, CDCl3) 14.5 (CH3), 27.1 (CH3), 39.2 (CC=O), 64.7 (-OCH2-), 89.4 (C-2),
113.3 (C-6), 133.1 (C-3), 134.0 (C-1), 145.8 (C-4), 151.6 (C-5), 175.7 (C=O), 195.0 (CHO);
IR (KBr, cm−1) 1685 (C=O), 1759; MS (EI): m/z 377 [M+H+].
3.5. General Procedure for the Synthesis of 16–18, 23 and 24
To the appropriate iodinated compound (2 mmol) was added Cu2O (0.1 mmol), pyridine-2-aldoxime
(0.2 mmol), tetrabutylammonium bromide (0.4 mmol), cesium hydroxide monohydrate (10 mmol), and
water (2 mL) and the mixture was stirred under N2 atmosphere for 10 h. The reaction mixture was
acidified to pH 5–7 with 1 M hydrochloric acid. The aqueous layer was extracted with
dichloromethane (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium
sulfate, and filtered; the solvent was then removed in vacuo. Column chromatography (petroleum
ether-ethyl acetate: 20:1) afforded the corresponding phenol.
2,4-Dihydroxy-3,5-dimethoxybenzaldehyde (16, C9H10O5). Yellow solid. Yield: 90%. mp (°C): 87.5–89.8.
1H-NMR (500 MHz, CDCl3): 3.91 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 6.41 (s, 1H, Ar), 6.75 (s, 1H,
13
OH), 9.70 (s, 1H, OH), 11.30 (s, 1H, CHO); C-NMR (75 MHz, CDCl3) 56.6 (OCH3), 60.9 (OCH3),
108.9 (C-6), 112.9 (C-1), 134.6 (C-3), 141.2 (C-4), 146.9 (C-2), 151.6 (C-5), 194.6 (CHO);
IR (KBr, cm−1) 3350 (br, OH), 1650 (C=O); MS (EI): m/z 199 [M+H+].

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2,4-Dihydroxy-5-methoxybenzaldehyde (17, C8H8O4). Yellow solid. Yield: 77%. mp (°C): 152.1−153.2.
1H-NMR (500 MHz, CDCl3): 3.92 (s, 3H, OCH3), 6.41 (s, 1H, Ar), 6.53 (s, 1H, Ar), 6.89 (s, 1H, OH),
9.68 (s, 1H, OH), 11.34 (s, 1H, CHO); 13C-NMR (75 MHz, CDCl3) 56.5 (OCH3), 103.2 (C-3),
112.9 (C-1), 113.3 (C-6), 140.7 (C-5), 154.4 (C-4), 159.6 (C-2), 193.8 (CHO); IR (KBr, cm−1)
3292 (br, OH), 1635 (C=O); MS (EI): m/z 169 [M+H+].
5-Ethoxy-2,4-dihydroxybenzaldehyde (18, C9H10O4). Yellow solid. Yield: 77%. mp (°C): 131.8−134.4.
1H-NMR (500 MHz, CDCl3): 1.47 (t, J = 7.0 Hz, 3H, CH3), 4.12 (q, J = 7.0 Hz, 2H, OCH2-),
13
6.49 (s, 1H, Ar), 6.53 (s, 1H, Ar), 6.88 (s, 1H, OH), 9.65 (s, 1H, OH), 11.33 (s, 1H, CHO); C-NMR
(75 MHz, CDCl3) 14.8 (CH3), 65.3 (-CH2O), 103.1 (C-3), 113.3 (C-1), 113.9 (C-6), 139.9 (C-5),
154.6 (C-4), 159.5 (C-2), 193.8 (CHO); IR (KBr, cm−1) 1627 (C=O), 1699, 3367 (br, OH); MS (EI):
m/z 183 [M+H+].
2-Hydroxy-3,4,5-trimethoxybenzaldehyde (23, C10H12O4). Yellow solid. Yield: 83%. mp (°C): 46.0–46.6.
1H-NMR (500 MHz, CDCl3): 3.87 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.05 (s, 3H, OCH3),
6.78 (s, 1H), 9.78 (s, 1H, OH), 11.01 (s, 1H, CHO); 13C-NMR (75 MHz, CDCl3) 61.4 (OCH3),
61.1 (OCH3), 56.5 (OCH3), 109.2 (C-6), 115.2 (C-1), 141.0 (C-3), 146.3 (C-4), 150.3 (C-2),
151.8 (C-5), 194.9 (CHO); IR (KBr, cm−1) 1641 (C=O), 3240 (br, OH); MS (EI): m/z 213 [M+H+].
2-Hydroxy-4,5-dimethoxybenzaldehyde (24, C9H10O3). Yellow solid. Yield: 85%. mp (°C): 105.5–112.8.
1H-NMR (500 MHz, CDCl3): 3.88 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 6.48 (s, 1H, Ar), 6.91 (s, 1H,
13
Ar), 9.71 (s, 1H, OH), 11.40 (s, 1H, CHO); C-NMR (75 MHz, CDCl3) 56.4 (OCH3), 56.4 (OCH3),
100.1 (C-3), 112.9 (C-1), 113.2 (C-6), 143.0 (C-5), 157.2 (C-2), 159.4 (C-4), 194.0 (CHO);
IR (KBr, cm−1) 1624 (C=O), 3446 (br, OH); MS (EI): m/z 183 [M+H+].
4. Conclusions
A novel method for the total synthesis of six coumarins and five important intermediates has been
developed. In most cases, the overall yields of these products are higher than those previously
reported. Furthermore, this is the first reported total synthesis of 7-hydroxy-6-ethoxycoumarin (3) and
6,7,8-trimethoxycoumarin (4). All of these coumarins and advanced intermediates will be evaluated for
their activity, and the results will be reported in due course.
Acknowledgments
This work was financially supported by Fundamental Research Funds for the Central Universities
(DL12EA01) and the Heilongjiang Postdoctoral Scientific Research Fund (LBH-Q11182).
Conflicts of Interest
The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 1–6 are available from the authors.
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