A convenient synthesis of dihydrocoumarins from phenols and cinnamic acid derivatives

Tetrahedron 61 (2005) 9291–9297

A convenient synthesis of dihydrocoumarins from phenols and cinnamic acid derivatives Shinya Aoki, Chie Amamoto, Juzo Oyamada and Tsugio Kitamura* Department of Chemistry and Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi, Saga 840-8502, Japan Received 27 June 2005; revised 16 July 2005; accepted 19 July 2005 Available online 9 August 2005

Abstract—A facile procedure for synthesis of dihydrocoumarin derivatives was described. Although the yield of the products in the reaction of phenols with acrylates in trifluoroacetic acid in the presence of Pd(OAc)2 giving coumarins was found to be very low, dihydrocoumarin derivatives were obtained in good to high yields in the absence of Pd(OAc)2 when ethyl cinnamates bearing electron-donating groups were employed in this reaction. q 2005 Elsevier Ltd. All rights reserved.

1. Introduction 4-Aryl-3,4-dihydrocoumarins are of synthetic interest because they are present in a number of natural molecules, such as 4-aryl-3,4-dihydrocoumarins (neoflavonoids),1 complex flavonoids,2 and 1-arylbenzo[f]chroman-3-ones.3 Although many synthetic methods for 4-aryl-3,4-dihydrocoumarins have been reported up to the present, most of the procedures based on the condensation of phenols with cinnamic acids have been conducted in strong acidic media and at high temperature.4 Consequently, a mild and simple procedure is strongly desired. Recently, it has been found that hydroarylation of alkynes takes place in the presence of a palladium or platinum catalyst under mild conditions in trifluoroacetic acid (TFA) (Eq. 1).5 This hydroarylation reaction efficiently proceeds intramolecularly to afford heterocycles, such as coumarins, quinolines, and thiocoumarins.5,6 Interestingly, this hydroarylation reaction has been applied to direct synthesis of coumarins from phenols and propiolic acids or esters (Eq. 2).7 However, the palladium-catalyzed reaction of phenols with ethyl acrylates does not afford dihydrocoumarins via hydroarylation but coumarins derived from the Heck-type coupling reaction followed by intramolecular cyclization (Eq. 3).8 During the course of our study on hydroarylation reactions, we found that dihydrocoumarins were formed without palladium catalysts when electron-rich cinnamic acids and esters were Keywords: Dihydrocoumarins; Phenols; Cinnamic acid derivatives; Trifluoroacetic acid. * Corresponding author. Tel.: C81 952288550; fax: C81 952288548; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.07.062

employed in the hydroarylation reaction.9 This procedure provides a very mild and convenient method for synthesis of 4-aryl-3,4-dihydrocoumarins. Here we wish to report our findings concerning the synthesis of 4-aryl-3,4-dihydrocoumarins from phenols and electron-rich cinnamic acids and esters.10 (1)

(2)

(3)

2. Results and discussion 2.1. Reaction of ethyl 4-methoxycinnamate (1a) with phenols 2 First, the reaction of ethyl 4-methoxycinnamate (1a) as an electron-rich substrate with 2-naphthol (2a) was examined (Table 1). After dissolving 1a and 2a in TFA, the mixture was stirred for 24 h at rt. Workup (neutralization and extraction)

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followed by purification (column chromatography on silica gel) gave 1,2-dihydro-1-(4-methoxyphenyl)-3H-naphtho[2,1-b]pyran-3-one (3aa) quantitatively. This reaction is a very simple and useful method that provides a sophisticated dihydrocoumarin derivative in high yield.

dihydrocoumarin (3aj), quite differing from the electron-rich phenols. However, it is expected that the reaction at an elevated temperature for a longer time increases the yield of dihydrocoumarins 3, as observed in the literature.10

Similar reactions with 3,4-methylenedioxyphenol (2b), 3,5-dimethoxyphenol (2c), and 3-methoxyphenol (2d) gave the corresponding dihydrocoumarins 3ab, 3ac, and 3ad in high yields, respectively. However, the reaction with 4-methoxyphenol (2e) afforded 6-methoxy-4-(4methoxyphenyl)-3,4-dihydrocoumarin (3ae) only in 32% yield. The methoxy group of 2e deactivates the reaction site, the ortho position to the hydroxyl group, by an inductive effect. In the reaction of 1a with 3,4dimethylphenol (2f) and 3,5-di-methylphenol (2g), the corresponding dihydrocoumarins 3af and 3ag were obtained in high yields, respectively. The reactions with cresols, such as 3-methylphenol (2h) and 4-methylphenol (2i), gave dihydrocoumarins 3ah and 3ai in 60 and 71% yields, respectively. An electron-deficient phenol, 4-bromophenol (2j), afforded only 8% yield of

2.2. Substituent effect on the formation of dihydrocoumarins 3 in the reaction of ethyl cinnamates 1 with phenols 2 To apply the reaction to the synthesis of several substituted dihydrocoumarins 3, various substituted ethyl cinnamates 1 were employed in the reaction with 2-naphthol (2a) (Table 2 and Fig. 1). In the case of 1 bearing electron-rich aryl groups such as 4-methoxyphenyl (1a), 3,4-dimethoxyphenyl (1b), and 3-hydroxy-4-methoxyphenyl (1c), dihydrocoumarins 3aa, 3ba, and 3ca were obtained quantitatively, whereas the reaction of ethyl 4-methylcinnamate (1d) afforded only 43% yield of dihydrocoumarin 3da. In the cases of the substrates bearing a methyl group at the ortho position such as ethyl 2,5-dimethycinnamate (1g) and 2,4,6-trimethycinnamate (1h), no dihydrocoumarins 3 were obtained and the starting

Table 1. Reaction of 1a with phenols 2a

Run

1

Phenol 2

Product 3

2a

Yield (%)

Run

100

6

Phenol 2

Product 3

Yield (%)

100 3af

3aa 2f

100

2

7

98 2g

3ab

3ag

2b

86

3 2c

3ac

2d

3ad

60 2h

71

4

8 3ah

9

71 3ai 2i

32

5

8

10 3aj

3ae 2e a

A solution of 1a (1 mmol) and 2 (1 mmol) in TFA (1 mL) was stirred at rt for 24 h.

2j

S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297

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Table 2. Substituent effect of cinnamate 1 on the formation of dihydrocoumarins 3a

Entry

Cinnamate 1, Ar

1

1b:

2

1b

Phenol 2

2a

Dihydrocoumarin 3 (%)

3ba 100

3bf 100 2f

3

3bg 100

1b 2g

4

1c:

2a

3ca 100

5 6

1c 1c

2f 2g

3cf 100 3cg 97

7

1d:

2a

3da 43

8

1d

2b

3db 9

9

1e:

2a

3ea 20

10

1f:

2a

3fa 100

a

A solution of 1 (1 mmol) and 2 (1 mmol) in TFA (1 mL) was stirred at rt for 24 h.

materials were recovered. The parent ethyl cinnamate (1i) also did not undergo any reaction under the same conditions.

2.3. Reaction in a mixed solvent of TFA and 1,2-dichloroethane

On the other hand, the combination of electron-rich cinnamates 1b,c and electron-rich phenols 2f,g gave almost quantitative yields of dihydrocoumarins 3bf, 3bg, 3cf, and 3cg, respectively.

Although the reaction proceeded efficiently in TFA solvent at rt, we examined a decrease of the amount of TFA in a mixed solvent of TFA and 1,2-dichloroethane (Table 3). When the reaction of 1a with 2g was conducted in a 1:1

Figure 1. Dihydrocoumarins 3 listed in Table 2.

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S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297 Table 4. Reaction of 4-methoxycinnamic acid 4 with phenols 2a

Table 3. Effect of the amount of TFA

Solvent TFA (mL)

ClCH2CH2Cl (mL)

1 0.5 0.3 0.1

0 0.5 0.7 0.9

Yield (%)

98 93 58 5

mixture (v/v) of TFA and 1,2-dichloroethane, dihydrocoumarin 3ag was obtained in 93% yield. Further decrease in the ratio of TFA resulted in a significant decrease in the yield of 3ag, as seen from Table 3. 2.4. Reaction of 4-methoxycinnamic acid (4) with phenols 3 To extend the above reaction, we examined the reaction of 4-methoxycinnamic acid (4) instead of ethyl ester 1a (Table 4).10 On the basis of the reaction in a mixture of TFA and 1,2-dichloroethane, we conducted the reaction of 4 in a 2:1 mixture (v/v) of TFA and CH2Cl2. When the reaction of 4 with 3,5-dimethylphenol (2g) was carried out in a mixed solvent of TFA (1 mL) and CH2Cl2 (0.5 mL) at rt for 24 h, dihydrocoumarin 3ag was obtained quantitatively. Similarly, the reaction with 3,4-dimethyphenol (2f) gave dihydrocoumarin 3af quantitatively, while the reaction with 3-methylphenol (2h) decreased the yield of dihydrocoumarin 3ah (47%). Apparently, the reaction with electron-rich phenols, such as 2-naphthol (2a), 3,4-methylenedioxyphenol (2b), 3,4-dimethoxyphenol (2c), and 3-methoxyphenol (2d), afforded the corresponding dihydrocoumarins 3 in high yields. In the case of the reaction with 4-methoxyphenol (2e), however, a lower yield (38%) of dihydrocoumarin 3ae was observed for the reason similar to the reaction of 1a with 2e. When the reaction of 4 with phenol (2k) was conducted under similar conditions, dihydrocoumarin 3ak was obtained in 13% yield, together with 85% yield of 3-(4-hydroxyphenyl)-3-(4-methoxyphenyl)propionic acid (5).

Scheme 1.

Entry

Phenol 2

Dihydrocoumarin 3

Isolated yield (%)

1 2 3 4 5 6 7 8 9

2a 2b 2c 2d 2e 2f 2g 2h 2k

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ak

85 99 90 72 38 100 100 47 13b

a

A solution of 4 (1 mmol) and 2 (1 mmol) in TFA (1 mL) and CH2Cl2 (0.5 mL) was stirred at rt for 24 h. b 3-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)propionic acid (5) was also formed in 85% yield

.

2.5. Mechanistic consideration The role of TFA is important in the reaction of cinnamates 1 with phenols 2, as seen from Table 3. Scheme 1 shows a possible mechanism of the formation of dihydrocoumarins 3, where the reaction is promoted by protonation of 1 with TFA. Accordingly, electron-donating groups on 1 stabilize the resulting cationic intermediate 6 and facilitate the further reaction. However, an unsubstituted phenyl group is not enough to react with phenols 2. Since the phenyl groups with the ortho methyl substituent cannot participate in the stabilization of the cationic intermediate 6 because of steric hindrance, no products are formed. A similar substituent

S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297

effect is also observed in the case of phenols 2. As expected, the reaction with 4-bromophenol (2j) results in the low yield of 3. The electrophilic substitution of phenol 2 by the cationic intermediate 6 gives 3-(2-hydroxyphenyl)propiolate 7, which immediately undergoes intramolecular transesterification to lead to dihydrocoumarin 3. The electrophilic substitution of phenol (2k) occurs at the para position to afford 3-(4-hydroxyphenyl)propionic acid (5) predominantly. The behavior of the cationic intermediate 6 toward the phenol is very close to the result of the Friedel–Crafts alkylation of phenol that shows the predominant formation of para products.11

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NMR (CDCl3, 75.5 MHz) d 36.64, 37.45, 55.02, 114.43, 117.37, 117.90, 122.95, 125.09, 127.29, 127.86, 128.58, 129.65, 130.83, 130.93, 132.42, 149.52, 158.75, 167.15. 4.2.2. 4-(4-Methoxyphenyl)-6,7-methylenedioxy-3,4dihydrocoumarin (3ab). Mp 136.5–137.5 8C (CH2Cl2/ hexane) (lit.6 mp 134.6–135.2 8C). 1H NMR (CDCl3, 300 MHz) d 2.91 (dd, JZ15.8, 8.0 Hz, 1H, CH), 3.00 (dd, JZ15.7, 6.0 Hz, 1H, CH), 3.79 (s, 3H, OMe), 4.16 (app. t, JZ 6.8 Hz, 1H, CH), 5.93 (s, 2H, CH2), 6.38 (s, 1H, ArH), 6.63 (s, 1H, ArH), 6.86 (app. d, JZ8.7 Hz, 2H, ArH), 7.05 (app. d, JZ 8.7 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.14, 39.82, 55.26, 99.06, 101.64, 107.21, 114.48, 118.38, 128.49, 132.35, 144.36, 146.10, 147.41, 158.99, 167.67.

3. Conclusion During the course of study on our hydroarylation reactions, we found a convenient and efficient synthesis of 4-aryl-3,4dihydrocoumarins. This process is conducted under very mild conditions by using electron-rich cinnamic acid derivatives 1 (or 4) and electron-rich phenols 2. The convenient procedure involves only a simple mixing of 1 (or 4) and 2 in TFA at rt, followed by separation by column chromatography. Because of the simplicity and mildness, this procedure is applicable for a variety of 4-aryl-3,4-dihydrocoumarins, along with the previously reported methods (Table 4). 4. Experimental 4.1. General Melting points were measured with a Yanaco micromelting apparatus and are not corrected. 1H and 13C NMR spectra were recorded on a JEOL AL 300 spectrometer; chemical shifts (d) are reported in parts per million relative to tetramethylsilane. Column chromatography was carried out on silica gel (Silica Gel 60, spherical, Kanto Chemical Co.) with hexane and ethyl acetate as an eluent. Elemental analyses were conducted by the Service Center of the Elemental Analysis of Organic Compounds, Faculty of Science, Kyushu University. 4.2. General procedure for the reaction of cinnamates 1 with phenols 2 In a test tube was placed an ethyl cinnamate 1 (1 mmol), a phenol 2 (1 mmol), and TFA (1 mL). The mixture was stirred at rt for 24 h. The reaction mixture was neutralized with aqueous NaHCO3 and extracted with CH2Cl2. The product was separated by column chromatography on silica gel and purified by recrystallization from CH2Cl2/hexane. A similar procedure was also followed when the reaction of 4-methoxycinnamic acid (4) was conducted in a mixed solvent of TFA (1 mL) and CH2Cl2 (0.5 mL). 4.2.1. 1,2-Dihydro-1-(4-methoxyphenyl)-3H-naphtho[2,1-b]pyran-3-one (3aa).4e Mp 130.0–131.0 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 3.11 (dd, JZ15.6, 2.9 Hz, 1H, CH), 3.20 (dd, JZ15.6, 6.0 Hz, 1H, CH), 3.72 (s, 3H, OMe), 4.90 (dd, JZ6.0, 2.7 Hz, 1H, CH), 6.78 (d, JZ8.7 Hz, 2H, ArH), 7.03 (app. d, JZ8.4 Hz, 2H, ArH), 7.33 (d, JZ8.7 Hz, 1H, ArH), 7.40–7.49 (m, 2H, ArH), 7.79 (d, JZ8.4 Hz, 1H, ArH), 7.85 (d, JZ8.7 Hz, 2H, ArH). 13C

4.2.3. 5,7-Dimethoxy-4-(4-methoxyphenyl)-3,4-dihydrocoumarin (3ac). Mp 133.3–133.8 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.97 (d, JZ4.2 Hz, 2H, CH2), 3.74 (s, 6H, 2OMe), 3.81 (s, 3H, OMe), 4.50 (t, JZ4.5 Hz, 1H), 6.27 (d, JZ2.1 Hz, 1H, ArH), 6.31 (d, JZ2.4 Hz, 1H, ArH), 6.78 (d, JZ8.4 Hz, 1H, ArH), 7.02 (d, JZ8.7 Hz, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 33.67, 37.25, 55.18, 55.53, 55.79, 93.94, 95.08, 106.41, 114.17, 127.74, 133.57, 153.00, 157.36, 158.57, 160.58, 167.74. Anal. Calcd for C18H18O5: C, 68.78; H, 5.77. Found: C, 68.89; H, 5.81. 4.2.4. 7-Methoxy-4-(4-methoxyphenyl)-3,4-dihydrocoumarin (3ad).4o Mp 143.6–144.9 8C (CH2Cl2/hexane). 1 H NMR (CDCl3, 300 MHz) d 2.94 (dd, JZ15.8, 8.0 Hz, 1H, CH), 3.03 (dd, JZ15.8, 5.9 Hz, 1H, CH), 3.786 (s, 3H, OMe), 3.794 (s, 3H, OMe), 4.23 (app. t, JZ6.6 Hz, 1H, CH), 6.63 (dd, JZ8.4, 2.4 Hz, 1H, ArH), 6.66 (d, JZ 2.1 Hz, 1H, ArH), 6.85–6.88 (m, 3H, ArH), 7.06 (app. d, JZ 8.7 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.47, 39.30, 55.26, 55.51, 102.48, 110.68, 114.43, 118.04, 128.51, 128.81, 132.70, 152.39, 158.92, 159.94, 167.72. 4.2.5. 6-Methoxy-4-(4-methoxyphenyl)-3,4-dihydrocoumarin (3ae). Mp 87.8–89.6 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.94 (dd, JZ15.9, 7.8 Hz, 1H, CH), 3.03 (dd, JZ15.75, 6 Hz, 1H, CH), 3.71 (s, 3H, OMe), 3.79 (s, 3H, OMe), 4.24 (t, JZ6.9 Hz, 1H, CH), 6.49 (d, JZ 6 Hz, 1H, ArH), 6.81 (dd, JZ8.9, 3.2 Hz, 1H, ArH), 6.87 (app. d, JZ8.7 Hz, 2H, ArH), 7.04–7.10 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.11, 40.14, 55.25, 55.57, 113.37, 113.61, 114.46, 117.77, 127.18, 128.57, 132.04, 145.56, 156.27, 158.97, 167.91. Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found: C, 71.86; H, 5.65. 4.2.6. 4-(4-Methoxyphenyl)-6,7-dimethyl-3,4-dihydrocoumarin (3af).4j Mp 126.5–127.9 8C (CH2Cl2/hexane). 1 H NMR (CDCl3, 300 MHz) d 2.15 (s, 3H, Me), 2.24 (s, 3H, Me), 2.92 (dd, JZ15.8, 7.4 Hz, 1H, CH), 3.00 (dd, JZ15.6, 6.0 Hz, 1H, CH), 3.78 (s, 3H, OMe), 4.21 (t, JZ6.8 Hz, 1H, CH), 6.72 (s, 1H, ArH), 6.85 (app. d, JZ9.0 Hz, 2H, ArH), 6.89 (s, 1H, ArH), 7.05 (app. d, JZ8.4 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 19.00, 19.50, 37.50, 39.62, 55.23, 114.38, 117.79, 122.94, 128.48, 128.91, 132.76, 132.84, 137.27, 149.59, 158.85, 168.10. 4.2.7. 4-(4-Methoxyphenyl)-4,7-dimethyl-3,4-dihydrocoumarin (3ag).4j Mp 170.6–171.2 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.14 (s, 3H, Me), 2.32 (s, 3H,

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Me), 2.97 (dd, JZ15.8, 3.2 Hz, 1H, CH), 3.03 (dd, JZ15.3, 5.6 Hz, 1H, CH), 3.74 (s, 3H, OMe), 4.32 (dd, JZ5.6, 3.2 Hz, 1H, CH), 6.79 (d, JZ8.6 Hz, 2H, ArH), 6.83 (br s, 2H, ArH), 6.95 (d, JZ8.6 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 18.53, 20.99, 37.13, 37.89, 55.15, 114.38, 115.32, 120.43, 127.21, 127.94, 132.28, 136.48, 138.58, 151.97, 158.74, 167.54. 4.2.8. 4-(4-Methoxyphenyl)-7-methyl-3,4-dihydrocoumarin (3ah).12 Mp 85–87 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.34 (s, 3H, Me), 2.93 (dd, JZ15.2, 8.1 Hz, 1H, CH), 3.01 (dd, JZ15.6, 6.6 Hz, 1H, CH), 3.77 (s, 3H, OMe), 4.23 (app. t, JZ6.9 Hz, 1H, CH), 6.84–6.92 (m, 5H, ArH), 6.95 (app. d, JZ9.0 Hz, 2H, ArH). 13 C NMR (CDCl3, 75.5 MHz) d 20.97, 37.30, 39.51, 55.21, 114.38, 117.38, 123.01, 125.33, 127.93, 128.49, 132.47, 138.94, 151.44, 158.86, 168.08. 4.2.9. 4-(4-Methoxyphenyl)-6-methyl-3,4-dihydrocoumarin (3ai).12 Mp 120.2–120.6 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.24 (s, 3H, Me), 2.93 (dd, JZ15.2, 7.5 Hz, 1H, CH), 3.00 (dd, JZ15.6, 7.5 Hz, 1H, CH), 3.77 (s, 3H, OMe), 4.22 (t, JZ6.8 Hz, 1H, CH), 6.77 (s, 1H, ArH), 6.86 (app. d, JZ8.7 Hz, 2H, ArH), 6.99 (d, JZ8.4 Hz, 1H, ArH), 7.03–7.07 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 20.71, 37.28, 39.92, 55.24, 114.34, 116.77, 125.74, 128.54, 128.56, 129.15, 132.43, 134.22, 149.57, 158.92, 167.91. 4.2.10. 7-Bromo-4-(4-methoxyphenyl)-3,4-dihydrocoumarin (3aj). Mp 149.5–150.5 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.96 (dd, JZ16.1, 8.3 Hz, 1H, CH), 3.04 (dd, JZ15.8, 6.2 Hz, 1H, CH), 3.81 (s, 3H, OMe), 4.26 (app. t, JZ7.2 Hz, 1H, CH), 6.89 (app. d, JZ8.7 Hz, 2H, ArH), 7.00 (d, JZ8.4 Hz, 1H, ArH), 7.05–7.09 (m, 3H, ArH), 7.40 (dd, JZ8.7, 2.4 Hz, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 36.78, 39.82, 55.32, 114.69, 117.29, 118.84, 128.44, 128.57, 131.02, 131.26, 131.72, 150.72, 159.22, 166.94. Anal. Calcd for C16H13BrO3: C, 57.68; H, 3.93. Found: C, 57.77; H, 3.94. 4.2.11. 4-(4-Methoxyphenyl)-3,4-dihydrocoumarin (2ak).12 Mp 136.9–138.1 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 2.98 (dd, JZ16.2, 7.8 Hz, 1H, CH), 3.53 (dd, JZ17.4, 6.0 Hz, 1H, CH), 3.79 (s, 3H, OMe), 4.30 (t, JZ6.8 Hz, 1H), 6.87 (app. d, JZ8.7 Hz, 2H, ArH), 6.98 (d, JZ7.5 Hz, 1H, ArH), 7.06–7.13 (m, 4H, ArH), 7.29 (td, JZ7.8, 1.8 Hz, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.19, 39.90, 55.28, 114.48, 117.08, 124.60, 126.20, 128.26, 128.60, 128.68, 132.20, 151.66, 159.00, 167.73. 4.2.12. 1,2-Dihydro-1-(3,4-dimethoxyphenyl)-3Hnaphtho[2,1-b]pyran-3-one (3ba). 13 Mp 156–159 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 3.14 (dd, JZ3.0, 15.3 Hz, 1H, CH), 3.20 (dd, JZ5.7, 15.3 Hz, 1H, CH), 3.78 (s, 3H, OMe), 4.90 (dd, JZ3.0, 5.7 Hz, 1H, CH), 6.57– 6.60 (m, 1H, ArH), 6.69–6.72 (m, 2H, ArH), 7.33–7.51 (m, 3H, ArH), 7.80–7.88 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.14, 37.49, 55.70, 55.74, 110.05, 11.56, 117.34, 117.76, 118.94, 122.94, 125.13, 127.32, 128.61, 129.75, 130.88, 130.95, 132.97, 148.34, 149.39, 149.55, 167.15. 4.2.13. 1,2-Dihydro-1-(4-hydroxy-3-methoxyphenyl)3H-naphtho[2,1-b]pyran-3-one (3ca).14 Mp 150.4– 151.4 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d

3.12 (dd, JZ2.7, 10.6 Hz, 1H, CH), 3.19 (dd, JZ4.0, 10.6 Hz, 1H, CH), 3.76 (s, 3H, OMe), 4.89 (dd, JZ2.7, 4.0 Hz, 1H, CH), 5.52 (s, 1H, OH), 6.60–6.62 (m, 2H, ArH), 6.77–6.80 (m, 1H, ArH), 7.32–7.51 (m, 3H, ArH), 7.79– 7.82 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.20, 37.58, 55.69, 109.17, 114.79, 117.31, 117.82, 119.68, 122.96, 125.14, 127.32, 128.59, 129.74, 130.88, 130.96, 132.37, 144.94, 146.96, 149.51, 167.31. 4.2.14. 1,2-Dihydro-1-(4-methylphenyl)-3H-naphtho[2,1-b]pyran-3-one (3da). Mp 108.5–109.5 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 2.26 (s, 3H, Me), 3.13 (dd, JZ15.9, 2.7 Hz, 1H, CH), 3.20 (dd, JZ15.9, 6.6 Hz, 1H, CH), 4.92 (app. d, JZ3.9 Hz, 1H, CH), 6.99– 7.08 (m, 4H, ArH), 7.34 (d, JZ9.0 Hz, 1H, ArH), 7.40–7.49 (m, 2H, ArH), 7.79 (d, JZ7.8 Hz, 1H, ArH), 7.85 (d, JZ 9.0 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 20.87, 37.19, 37.44, 117.45, 117.80, 123.01, 125.12, 126.71, 127.34, 128.64, 129.71, 129.80, 130.95, 131.01, 137.12, 137.49, 149.67, 167.12. Anal. Calcd for C20H16O2: C, 83.31; H, 5.59. Found: C, 83.41; H, 5.58. 4.2.15. 4-(3,4-Dimethoxyphenyl)-6,7-dimethyl-3,4-dihydrocoumarin (3bf). Mp 141.7–142.8 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 2.15 (s, 3H, Me), 2.24 (s, 3H, Me), 2.94 (dd, JZ15.8, 7.4 Hz, 1H, CH), 3.01 (dd, JZ15.8, 5.9 Hz, 1H, CH), 3.82 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.21 (t, JZ6.6 Hz, 1H, CH), 6.66–6.68 (m, 2H, ArH), 6.74 (s, 1H, ArH), 6.81 (app. d, JZ8.7 Hz, 1H, ArH), 6.89 (s, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 18.87, 19.37, 37.33, 39.91, 55.75 (2OMe), 110.45, 111.43, 117.63, 119.34, 122.70, 128.78, 132.76, 133.17, 137.19, 148.22, 149.20, 149.42, 168.05. Anal. Calcd for C19H20O4: C, 73.06; H, 6.45. Found: C, 73.00; H, 6.46. 4.2.16. 4-(4-Hydroxy-3-methoxyphenyl)-6,7-dimethyl-3, 4-dihydrocoumarin (3cf). Mp 141.7–142.8 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 2.15 (s, 3H, Me), 2.24 (s, 3H, Me), 2.92 (dd, JZ16.1, 7.4 Hz, 1H, CH), 3.00 (dd, JZ15.9, 6.0 Hz, 1H, CH), 3.82 (s, 3H, OMe), 4.19 (t, JZ 6.8 Hz, 1H, CH), 6.62–6.63 (m, 2H, ArH), 6.74 (s, 1H, ArH), 6.85 (d, JZ8.7 Hz, 1H, ArH), 6.89 (s, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 18.91, 19.41, 37.45, 40.00, 55.82, 139.77, 114.71, 117.66, 120.26, 122.82, 128.85, 132.55, 132.83, 137.23, 144.88, 146.86, 149.44, 168.24. Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.56; H, 6.12. 4.2.17. 4-(3,4-Dimethoxyphenyl)-5,7-dimethyl-3,4-dihydrocoumarin (3bg).15 Mp 137.9–138.9 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 2.16 (s, 3H, Me), 2.34 (d, 3H, Me), 2.94–3.08 (m, 2H, CH2), 3.80 (s, 3H, OMe), 3.82 (s, 3H, OMe), 4.29–4.32 (m, 1H, CH), 6.52 (d, JZ8.1 Hz, 1H, ArH), 6.59 (s, 1H, ArH), 6.73 (d, JZ8.1 Hz, 1H, ArH), 6.83 (br s, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 18.54, 20.98, 37.55, 37.87, 55.79 (2OMe), 110.16, 111.51, 115.28, 118.96, 120.25, 127.23, 132.83, 136.51, 138.64, 148.25, 149.30, 151.93, 167.59. 4.2.18. 4-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethyl-3, 4-dihydrocoumarin (3cg). Mp 176.8–177.6 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 2.16 (s, 3H, Me), 2.34 (s, 3H, Me), 2.97 (dd, JZ3.0, 15.6 Hz, 1H, CH), 3.03 (dd, JZ5.7, 15.6 Hz, 1H, CH), 3.79 (s, 3H, OMe), 4.30 (dd,

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JZ3.0, 5.7 Hz, 1H, CH), 5.53 (s, 1H, OH), 6.50–6.53 (m, 2H, ArH), 6.77–6.83 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 18.56, 21.02, 37.68, 38.00, 55.83, 109.25, 114.71, 115.33, 119.82, 120.34, 127.28, 132.24, 136.57, 138.68, 144.89, 146.91, 151.97, 167.69. Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.46; H, 6.08. 4.2.19. 6,7-Methylenedioxy-4-(4-methylphenyl)-3,4dihydrocoumarin (3db). Mp 131.6–132.4 8C (CH2Cl2/ hexane). 1H NMR (CDCl3, 300 MHz) d 2.33 (s, 3H, Me), 2.93 (dd, JZ15.9, 7.8 Hz, 1H, CH), 3.01 (dd, JZ15.8, 6.15 Hz, 1H, CH), 4.17 (t, JZ6.9 Hz, 1H, CH), 5.93 (s, 2H, CH2), 6.38 (s, 1H, ArH), 6.64 (s, 1H, ArH), 7.03 (d, JZ 8.1 Hz, 2H, ArH), 7.15 (d, JZ8.0 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 20.97, 37.01, 40.24, 99.06, 101.64, 107.26, 118.26, 127.31, 129.77, 137.37, 137.39, 144.37, 146.16, 147.43, 167.66. Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.38; H, 4.99.

2.

3. 4.

4.2.20. 1,2-Dihydro-1-(2,3,4-trimethoxyphenyl)-3Hnaphtho[2,1-b]pyran-3-one (3fa). Mp 178.0–178.4 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 3.08 (dd, JZ17.0, 3.6 Hz, 1H, CH), 3.15 (dd, JZ15.9, 6.6 Hz, 1H, CH), 3.75 (s, 3H, OMe), 3.90 (s, 3H, OMe), 4.09 (s, 3H, OMe), 5.23 (app. d, JZ4.2 Hz, 1H, CH), 6.35 (d, JZ 8.7 Hz, 1H, ArH), 6.40 (d, JZ8.7 Hz, 1H, ArH), 7.32 (d, JZ9.0 Hz, 1H, ArH), 7.40–7.49 (m, 2H, ArH), 7.76 (d, JZ 8.1 Hz, 1H, ArH), 7.85 (d, JZ8.7 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 31.59, 36.44, 55.72, 60.63, 60.98, 107.13, 117.34, 117.64, 121.89, 122.98, 125.05, 125.95, 127.27, 128.56, 129.58, 130.87, 130.97, 142.11, 150.03, 150.69, 153.22, 167.44. Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.30; H, 5.48. 4.2.21. 1,2-Dihydro-1-(3,4,5-trimethoxyphenyl)-3Hnaphtho[2,1-b]pyran-3-one (3ea). Mp 181.9–182.6 8C (CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 3.10– 3.24 (m, 2H, CH2), 3.72 (s, 6H, OMe), 3.77 (s, 3H, OMe), 4.87–4.90 (m, 1H, CH), 6.33 (s, 2H, ArH), 7.33–7.53 (m, 3H, ArH), 7.81–7.88 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.56, 37.97, 56.06, 60.72, 103.96, 117.42, 117.51, 123.02, 125.31, 127.50, 128.75, 130.04, 131.00, 131.07, 136.30, 137.40, 149.71, 153.72, 167.14. Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.15; H, 5.55. 4.2.22. 3-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)propionic acid (5). 1H NMR (CD3OD, 300 MHz) d 2.93 (d, JZ7.8 Hz, 2H, CH2), 3.73 (s, 3H, OMe), 4.35 (t, JZ8.0 Hz, 1H, CH), 6.68 (app. d, JZ6.5 Hz, 2H, ArH), 6.80 (app. d, JZ6.6 Hz, 2H, ArH), 7.04 (d, JZ8.1 Hz, 2H, ArH), 7.13 (d, JZ8.4 Hz, 2H, ArH). 13C NMR (CD3OD, 75.5 MHz) d 42.12, 46.92, 55.65, 114.79, 116.15, 129.60, 136.54, 137.86, 156.80, 159.57, 175.94. Anal. Calcd for C16H16O4: C, 70.58; H, 5.92. Found: C, 70.29; H, 6.01.

5.

6. 7.

8. 9. 10.

11. 12. 13.

References and notes 14. 1. (a) Donnelly, D. M. X.; Boland, G. M. Nat. Prod. Rep. 1995, 321. (b) Donnelly, D. M. X.; Boland, G. M. In The Flavonoids. Advances in Research Since 1986; Harborne, J. B., Ed.;

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