Scandium(III) triflate-catalyzed coumarin synthesis

Article abstract of DOI:10.1080/00397910802369513

Scandium(III) triflate is an excellent catalyst in the von Pechmann condensation. The solvent-free catalytic reactions proceed smoothly with a range of phenols and β-ketoesters in the presence of 10 mol% scandium(III) triflate at 80°C. This simple method affords various 4-substituted coumarins in good to excellent yield and is superior to the classical method in several aspects: solvent-free conditions, short reaction times, a decreased catalyst loading, a mild reaction temperature, and an easy workup. Copyright Taylor & Francis Group, LLC.

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Scandium(III) Triflate–Catalyzed
Coumarin Synthesis
Keumnyeo Jung a , Yun-Jeong Park a & Jae-Sang Ryu
a
a Division of Life and Pharmaceutical Sciences,
College of Pharmacy, Ewha Womans University ,
Seoul , Korea
Published online: 07 Nov 2008.
To cite this article: Keumnyeo Jung , Yun-Jeong Park & Jae-Sang Ryu (2008)
Scandium(III) Triflate–Catalyzed Coumarin Synthesis, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:24,
4395-4406, DOI: 10.1080/00397910802369513
To link to this article: http://dx.doi.org/10.1080/00397910802369513
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Synthetic Communications1, 38: 4395–4406, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369513
Scandium(III) Triflate–Catalyzed
Coumarin Synthesis
Keumnyeo Jung, Yun-Jeong Park, and Jae-Sang Ryu
Division of Life and Pharmaceutical Sciences, College of Pharmacy,
Ewha Womans University, Seoul, Korea
Abstract: Scandium(III) triflate is an excellent catalyst in the von Pechmann con-
densation. The solvent-free catalytic reactions proceed smoothly with a range of
phenols and b-ketoesters in the presence of 10 mol% scandium(III) triflate at
80 ꢀC. This simple method affords various 4-substituted coumarins in good to
excellent yield and is superior to the classical method in several aspects: solvent-
free conditions, short reaction times, a decreased catalyst loading, a mild reaction
temperature, and an easy workup.
Keywords: Coumarins, Pechmann reaction, phenols, Sc(OTf)3, solvent-free
INTRODUCTION
Coumarins, the most important classes of fluorescent molecules, consti-
tute important structural features present in a number of bioactive natural
products (Fig. 1). They exhibit a wide range of physiological activities,
such as anti-inflammatory,[1] antibacterial,[2] anticancer,[3] anticlotting,[4]
and anti-HIV activities.[5] Naturally, there have been continuous efforts
to develop new, convenient, and practical syntheses of coumarin and its
derivatives. The representative synthetic routes to coumarins include
Pechmann,[6] Knoevenagel,[7] Perkin,[8] Reformatsky,[9] and Wittig[10]
condensation reactions. Among these, Pechmann condensation is the
most widely used method for the syntheses of coumarins. This method
Received February 13, 2008.
Address correspondence to Jae-Sang Ryu, Division of Life and Pharmaceutical
Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-Dong,
Seodaemun-Gu, Seoul 120-750, Korea. E-mail: ryuj@ewha.ac.kr
4395

4396
K. Jung, Y.-J. Park, and J.-S. Ryu
Figure 1. Representative bioactive natural coumarins.
involves the reactions of various phenols and b-ketoesters in the presence
of an acid catalyst such as H2SO4,[11] HCl,[12] P2O5,[13] POCl3,[14] AlCl3,[15]
phosphoric acid,[16] or trifluoroacetic acid.[17] However, these conven-
tional methods require high temperatures (150 ꢀC or more), long reaction
times, and an excess amount of the acid catalyst. Especially, the produc-
tion of environmentally harmful acid waste makes chemists hesitate to
use this method for large-scale coumarin synthesis. In recent years, there
have been attempts to avoid this impediment and improve the conven-
tional methods by using microwave irradiation,[18] ionic liquid,[19] cation
exchange resins,[20] and Lewis acid catalysts.[21]
Over the past decade, scandium triflate [Sc(OTf)3] has drawn
chemists’ attention as a promoter in a variety of organic trans-
formations.[22] Sc(OTf)3 effectively activates carbonyl compounds as a
Lewis acid. While most Lewis acids are deactivated in the presence of
aqueous or protic solvents, Sc(OTf)3 is stable and works well even in
water.[22] This renders Sc(OTf)3 versatile, reusable, and environmentally
acceptable as a catalyst. Moreover, because of the small ionic radius
and strong Lewis acidity of Sc(III), Sc(OTf)3 shows high catalytic activ-
ities even compared to lanthanide triflate in some cases.[22] The unique
properties of Sc(OTf)3 prompted us to investigate the feasibility of the
Pechmann reaction. In the course of our work on the development of
efficient synthetic methods for polycyclic coumarins such as calanolides,
we have found an improved procedure for the one-pot construction of

Scandium(III) Triflate–Catalyzed Coumarin Synthesis
4397
Scheme 1. Scandium(III) triflate–catalyzed Pechmann reaction under solvent-free
conditions.
coumarin ring system. Herein, we report the studies on a Sc(OTf)3-
catalyzed, solvent-free, one-pot protocol for the syntheses of coumarins
(Scheme 1).
RESULTS AND DISCUSSION
As can be seen in Table 1, Sc(OTf)3 is an excellent catalyst in the Pech-
mann reaction of substituted phenols and b-ketoesters. The reactions
were found to be insensitive to air or moisture; hence there was no need
for an inert atmosphere. The reaction works for various b-ketoesters such
as ethyl acetoacetate, ethyl 4,4,4-trifluoroacetoacetate, ethyl benzoylace-
tate, and ethyl 3-oxohexanoate (Table 1, entries 1–4). In particular, the
reactions with ethyl acetoacetate, ethyl benzoylacetate, and ethyl 3-oxo-
hexanoate smoothly provide coumarins 1a, 1c, and 1d within a few hours,
which are key intermediates in the syntheses of polycyclic coumarin nat-
ural products: cordatolide, inophyllum, and calanolide, respectively. To
study the scope of this reaction, a series of Pechmann reactions with var-
ious phenols were carried out in the presence of Sc(OTf)3 (Table 1, entries
5–12). In all cases, the reactions proceeded successfully to afford the cor-
responding coumarins in good to excellent yields. The electron-donating
substituents in the meta position to the phenolic –OH facilitated the cycli-
zation. This observation can be explained by Scheme 2. After the trans-
esterification of the phenol, the electron-donating group can effectively
increase the nucleophilicity of the para position, where the subsequent
substitution occurs.
In a typical procedure, the solvent-free mixture of a phenol
(2.0 mmol) and a b-ketoester (2.4 mmol) in the presence of Sc(OTf)3
(0.2 mmol) was stirred in a preheated oil bath (80 ꢀC). Catalyst (10 mol%)
was sufficient to drive the reaction forward. Upon completion of the
reaction, a solid product was suspended in water, filtered, and recrystal-
lized in ethanol. The mother liquor was further purified by column

4398
K. Jung, Y.-J. Park, and J.-S. Ryu
Table 1. Scandium(III) triflate–catalyzed coumarin synthesis from phenols and
b-ketoesters.a
Entry
1
Substrate
Product
Time (h)
1
Yield (%)b
99
2
3
2
2
91
89
4
5
1
1
78
82
6
7
5.5
2
75
78
(Continued )

Scandium(III) Triflate–Catalyzed Coumarin Synthesis
4399
Table 1. Continued
Entry
8
Substrate
Product
Time (h)
4.5
Yield (%)b
83c
9
2
88
10
43
65c,d
11
12
1
81e
20
60f
aConditions: phenol (2.0 mmol), b-ketoester (2.4 mmol), and Sc(OTf)3
(0.2 mmol) were heated at 80 ꢀC.
bIsolated yield.
c1.5 equiv. of ethyl acetoacetate was employed to achieve efficient mixing.
dThe reaction was conducted at 120 ꢀC.
eThe structure was identified by NOESY and HMBC.
f3.0 equiv. of ethyl acetoacetate were employed to achieve efficient mixing.
chromatography. Conducting the reaction in a small amount of dioxane
was not effective. In fact, the reaction proceeded faster and more
efficiently under solvent-free conditions. In some cases, the reactions
suffered from inefficient mixing in the latter, once the solid product began
to form. Therefore, an excess of b-ketoester (1.5–3.0 equiv.) was
employed to effect thorough mixing (Table 1, entries 8, 10, and 12).

4400
K. Jung, Y.-J. Park, and J.-S. Ryu
Scheme 2. Plausible explanation for the substitution effect.
CONCLUSION
In conclusion, we have demonstrated a facile, one-step synthesis of cou-
marins using Sc(OTf)3 as a Lewis acid catalyst. Compared to the classical
methods, this efficient and simple method has several benefits: solvent-
free conditions, short reaction times, decreased catalyst loading, mild
reaction temperature, and an easy workup. We believe that because of
its advantages, the present catalytic method with versatile Sc(OTf)3
should find wide use in the synthesis of polycyclic natural coumarins.
EXPERIMENTAL
General Methods
Reagents were obtained from Aldrich Chemical (www.sigma-aldrich.-
com) and used without further purification. Thin-layer chromatography
(TLC) was performed on 0.25-mm E. Merck silica-gel 60 F254 plates and
visualized under UV light (254 nm) or by staining with potassium per-
manganate (KMnO4) or cerium ammonium molybdenate (CAM). Flash
chromatography was performed on E. Merck silica gel 60, 230–400 mesh.
NMR spectra were recorded on Varian Unity 400 instruments at 24 ꢀC.
Chemical shifts are expressed in parts per million (ppm) relative to
TMS (1H, 0 ppm), CDCl3 (13C, 77.0 ppm), or DMSO-d6 (1H, 2.50 ppm;
13C, 39.51 ppm); coupling constants are expressed in hertz. Mass spectra
were obtained with VG Trio-2 GC-MS instrument. High-resolution mass
spectra were obtained with a Jeol JMS-AX 505WA instrument.
General Procedure for Sc(OTf)3-Catalyzed Coumarin Synthesis
b-Ketoester (2.4 mmol) was added to a mixture of phenol (2.0 mmol) and
Sc(OTf)3 (98 mg, 0.2 mmol, 10 mol%) in a screw-cap vial. The reaction

Scandium(III) Triflate–Catalyzed Coumarin Synthesis
4401
mixture was stirred in a preheated oil bath (80 ꢀC). After the completion
of the reaction, the solid product was suspended in water (20 mL). The
resulting crude product was filtered off and recrystallized from hot EtOH
to give a white crystalline solid. The mother liquor was concentrated and
further purified by column chromatography (6:1 hexane=EtOAc) to
afford pure coumarin.
Data
5,7-Dihydroxy-4-methyl-2H-1-benzopyran-2-one (1a)
Yield: 99%. TLC: Rf 0.20 (1:1 hexane=EtOAc), mp 282–285 ꢀC (lit.[21c]
1
283–285 ꢀC). H NMR (400 MHz, DMSO-d6): d 10.51 (s, 1H), 10.28 (s,
1H), 6.25 (d, 1H, J ¼ 2.4), 6.16 (d, 1H, J ¼ 2.4), 5.85 (d, 1H, J ¼ 1.2),
2.49 (d, 1H, J ¼ 1.2). 13C NMR (100 MHz, DMSO-d6): d 161.0, 160.0,
157.9, 156.5, 154.9, 108.8, 102.1, 99.0, 94.5, 23.4. LRMS (FAB) m=z
193 ([M þ H]þ); HRMS (FAB): calcd. for C10H9O4 ([M þ H]þ),
193.0501; found, 193.0497.
5,7-Dihydroxy-4-(trifluoromethyl)-2H-1-benzopyran-2-one (1b)
Yield: 91%. TLC: Rf 0.45 (1:1 hexane=EtOAc), mp 250–251 ꢀC (lit.[21c]
1
250–252 ꢀC). H NMR (400 MHz, DMSO-d6): d 10.90 (s, 1H), 10.66 (s,
1H), 6.53 (s, 1H), 6.32 (d, 1H, J ¼ 2.4), 6.29 (d, 1H, J ¼ 2.4). 13C NMR
(100 MHz, DMSO-d6): d 162.4, 159.0, 157.0, 155.8, 139.5 (q, JCF ¼ 33.5),
121.4 (q, JCF ¼ 274), 110.6 (q, JCF ¼ 7.6), 99.5, 96.3, 95.2. LRMS (FAB)
m=z 247 ([M þ H]þ); HRMS (FAB): calcd. for C10H6F3O4 ([MþH]þ),
247.0218; found, 247.0212.
5,7-Dihydroxy-4-phenyl-2H-1-benzopyran-2-one (1c)
This product is well soluble in ethanol. Thus, the product was purified by
column chromatography (1:1 hexane=EtOAc). Yield: 89%. TLC: Rf 0.29
(1:1 hexane=EtOAc), mp 239–240 ꢀC (lit.[21b] 243–246 ꢀC). 1H NMR
(400 MHz, DMSO-d6): d 10.39 (s, 1H), 10.10 (s, 1H), 7.38–7.31 (m,
5H), 6.26 (d, 1H, J ¼ 2.0), 6.15 (d, 1H, J ¼ 2.0), 5.74 (s, 1H). 13C NMR
(100 MHz, DMSO-d6): d 161.7, 159.9, 157.1, 156.7, 156.0, 139.5, 127.7,
127.4, 127.2, 110.2, 100.5, 99.1, 94.6. LRMS (FAB) m=z 255 ([M þ H]þ);
HRMS (FAB): calcd. for C15H11O4 ([M þ H]þ), 255.0657; found,
255.0665.

4402
K. Jung, Y.-J. Park, and J.-S. Ryu
5,7-Dihydroxy-4-propyl-2H-1-benzopyran-2-one (1d)
Yield: 78%. TLC: Rf 0.35 (1:1 hexane=EtOAc), mp 238 ꢀC (lit.[23] 236–
238 ꢀC). 1H NMR (400 MHz, DMSO-d6): d 10.57 (s, 1H), 10.28 (s,
1H), 6.26 (d, 1H, J ¼ 2.4), 6.18 (d, 1H, J ¼ 2.4), 5.82 (s, 1H), 2.85 (t,
2H, J ¼ 7.6), 1.58 (m, 2H), 0.94 (t, 3H, J ¼ 7.6). 13C NMR (100 MHz,
DMSO-d6): d 160.9, 160.2, 158.5, 157.4, 156.9, 108.3, 101.4, 99.3, 94.7,
37.3, 22.6, 13.9. LRMS (FAB) m=z 221 ([M þ H]þ); HRMS (FAB): calcd.
for C12H13O4 ([M þ H]þ), 221.0814; found, 221.0813.
7-Hydroxy-4,8-dimethyl-2H-1-benzopyran-2-one (2a)
Yield: 82%. TLC: Rf 0.15 (2:1 hexane=EtOAc), mp 264 ꢀC (lit.[21b] 263–
1
265 ꢀC). H NMR (400 MHz, DMSO-d6): d 10.40 (s, 1H), 7.45 (d, 1H,
J ¼ 8.8), 6.86 (d, 1H, J ¼ 8.8), 6.12 (d, 1H, J ¼ 1.2), 2.36 (d, 3H,
J ¼ 1.2), 2.15 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d 160.4, 158.9,
153.7, 152.8, 123.1, 112.0, 111.7, 110.6, 109.9, 18.2, 8.0. LRMS (FAB)
m=z 191 ([M þ H]þ); HRMS (FAB): calcd. for C11H11O3 ([M þ H]þ),
191.0708; found, 191.0711.
7-Hydroxy-4-methyl-2H-1-benzopyran-2-one (3a)
This product is well soluble in ethanol. Thus, the product was purified by
column chromatography (2:1 hexane=EtOAc). Yield: 75%. TLC: Rf 0.19
(2:1 hexane=EtOAc), mp 185–187 ꢀC (lit.[21c] 184–186 ꢀC). 1H NMR
(400 MHz, DMSO-d6): d 10.51 (s, 1H), 7.60 (d, 1H, J ¼ 8.8), 6.80 (dd,
1H, J ¼ 8.8, 2.4), 6.70 (d, 1H, J ¼ 2.4), 6.13 (d, 1H, J ¼ 1.2), 2.37 (d,
3H, J ¼ 1.2). 13C NMR (100 MHz, DMSO-d6): d 161.1, 160.3, 154.8,
153.5, 126.6, 112.8, 112.0, 110.2, 102.2, 18.1. LRMS (FAB) m=z 177
([M þ H]þ); HRMS (FAB): calcd. for C10H9O3 ([M þ H]þ), 177.0552;
found, 177.0554.
5,7-Dimethoxy-4-methyl-2H-1-benzopyran-2-one (4a)
Yield: 78%. TLC: Rf 0.28 (2:1 hexane=EtOAc), mp 142–143 ꢀC (lit.[24]
1
143–145 ꢀC). H NMR (400 MHz, CDCl3): d 6.44 (d, 1H, J ¼ 2.4), 6.29
(d, 1H, J ¼ 2.4), 5.95 (d, 1H, J ¼ 1.2), 3.86 (s, 3H), 3.85 (s, 3H), 2.53
(d, 3H, J ¼ 1.2). 13C NMR (100 MHz, CDCl3): d 163.0, 161.3, 159.3,
157.2, 154.7, 111.6, 105.1, 95.7, 93.6, 56.0, 55.9, 24.4. LRMS (FAB)
m=z 221 ([M þ H]þ); HRMS (FAB): calcd. for C12H13O4 ([M þ H]þ),
221.0814; found, 221.0813.

Scandium(III) Triflate–Catalyzed Coumarin Synthesis
4403
7-Methoxy-4-methyl-2H-1-benzopyran-2-one (5a)
Yield: 83%. TLC: Rf 0.36 (2:1 hexane=EtOAc), mp 155–157 ꢀC (lit.[21c]
1
156–158 ꢀC). H NMR (400 MHz, CDCl3): d 7.50 (d, 1H, J ¼ 8.8), 6.87
(dd, 1H, J ¼ 8.8, 2.4), 6.83 (d, 1H, J ¼ 2.4), 6.14 (d, 1H, J ¼ 1.2), 3.88
(s, 3H), 2.40 (d, 3H, J ¼ 1.2). 13C NMR (100 MHz, CDCl3): d 162.9,
161.5, 155.6, 152.7, 125.7, 113.8, 112.5, 112.2, 101.1, 56.0, 18.9. LRMS
(FAB) m=z 191 ([M þ H]þ); HRMS (FAB): calcd. for C11H11O3
([M þ H]þ), 191.0708; found, 191.0710.
7,8-Dihydroxy-4-methyl-2H-1-benzopyran-2-one (6a)
Yield: 88%. TLC: Rf 0.22 (1:1 hexane=EtOAc), mp 240–247 ꢀC (lit.[21b]
1
241–243 ꢀC). H NMR (400 MHz, DMSO-d6): d 10.03 (s, 1H), 9.27 (s,
1H), 7.09 (d, 1H, J ¼ 8.8), 6.81 (d, 1H, J ¼ 8.8), 6.12 (d, 1H, J ¼ 1.2),
2.35 (d, 3H, J ¼ 1.2). 13C NMR (100 MHz, DMSO-d6): d 160.2, 154.0,
149.4, 143.3, 132.2, 115.5, 112.8, 112.1, 110.2, 18.3. LRMS (FAB) m=z
193 ([M þ H]þ).
7,8-Dimethoxy-4-methyl-2H-1-benzopyran-2-one (7a)
Yield: 65%. This product is very soluble in ethanol. Thus, the
product was purified by column chromatography (1:1 hexane=EtOAc).
TLC: Rf 0.16 (1:1 hexane=EtOAc), mp 125 ꢀC. 1H NMR (400 MHz,
DMSO-d6): d 7.50 (d, 1H, J ¼ 8.8), 7.12 (d, 1H, J ¼ 8.8), 6.23 (d, 1H,
J ¼ 1.6), 3.92 (s, 3H), 3.81 (s, 3H), 2.40 (d, 3H, J ¼ 1.6). 13C
NMR (100 MHz, DMSO-d6): d 159.7, 155.1, 153.6, 147.0, 135.2, 120.4,
114.2, 111.4, 108.8, 60.7, 56.3, 18.2. LRMS (FAB) m=z 221 ([M þ H]þ);
HRMS (FAB): calcd. for C12H13O4 ([M þ H]þ), 221.0814; found,
221.0813.
5-Hydroxy-4,7-dimethyl-2H-1-benzopyran-2-one (8a)
Yield: 81%. TLC: Rf 0.25 (3:1 hexane=EtOAc), mp 256–257 ꢀC. 1H NMR
(400 MHz, DMSO-d6): d 10.52 (s, 1H), 6.62 (d, 1H, J ¼ 1.2), 6.57 (d,
1H, J ¼ 1.2), 6.05 (d, 1H, J ¼ 1.2), 2.54 (d, 3H, J ¼ 1.2), 2.27 (s, 3H).
13C NMR (100 MHz, DMSO-d6): d 159.8, 156.4, 154.8, 154.6, 142.7,
111.9, 111.8, 107.7, 106.5, 23.4, 21.1. LRMS (FAB) m=z 191 ([M þ H]þ);
HRMS (FAB): calcd. for C11H11O3 ([M þ H]þ), 191.0708; found,
191.0704.

4404
K. Jung, Y.-J. Park, and J.-S. Ryu
6-Hydroxy-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (9a)
Yield: 60%. TLC: Rf 0.35 (1:1 hexane=EtOAc), mp 198–199 ꢀC. 1H NMR
(400 MHz, DMSO-d6): d 8.93 (s, 1H), 6.85 (s, 1H), 6.09 (d, 1H, J ¼ 1.2),
3.88 (s, 3H), 2.52 (d, 3H, J ¼ 1.2). 13C NMR (100 MHz, DMSO-d6): d
159.9, 153.5, 152.1, 147.5, 145.0, 136.5, 112.2, 107.3, 95.9, 60.4, 56.3,
22.2. LRMS (FAB) m=z 237 ([M þ H]þ); HRMS (FAB): calcd. for
C12H13O5 ([M þ H]þ), 237.0763; found, 237.0768.
ACKNOWLEDGMENTS
This work was supported by the Korea Research Foundation Grant
funded by the Korean Government (MOEHRD, Basic Research Promo-
tion Fund) (KRF-2006-331-E00438) and the second stage of the Brain
Korea 21 Project.
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