Convenient synthesis of a simple coumarin from salicylaldehyde and wittig reagent. IV: Improved synthetic method of substituted coumarins

Article abstract of DOI:10.3987/COM-02-S23

The reaction of salicylaldehydes (2) with Horner-Wadsworth-Emmons (HWE) or Ando-HWE reagents was attempted to afford intramolecular phosphonate derivatives (6). A new synthetic method for coumarins (1) was achieved by using protected 2.

Full text of DOI:10.3987/COM-02-S23

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 217 - 224, Received, 8th July, 2002
CONVENIENT SYNTHESIS OF A SIMPLE COUMARIN
FROM SALICYLALDEHYDE AND WITTIG REAGENT.
IV1a-c:
SUBSTITUTED COUMARINS †
IMPROVED
SYNTHETIC
METHOD
OF
Yasuo Takeuchi,* Norihiro Ueda, Koji Uesugi, Hitoshi Abe, Hiromi
Nishioka, and Takashi Harayama*
Faculty of Pharmaceutical Sciences, Okayama University, Okayama
700-8530, Japan
Abstract - The reaction of salicylaldehydes (2) with Horner-Wadsworth-
Emmons (HWE) or Ando-HWE reagents was attempted to afford
intramolecular phosphonate derivatives (6). A new synthetic method for
coumarins (1) was achieved by using protected 2.
Previously, we reported a convenient method for synthesizing a coumarin (1) by the Wittig reaction of a
variety of salicylaldehydes (2) with carbethoxymethylenetriphenylphosphorane (3) in N,N-diethylaniline
under reflux (Scheme 1).1a-c This method afforded the desired coumarin in high yield. However, there
was a problem in applying it to some coumarins, especially those with a substituent at the 6 or 8 position.
In this paper, we describe an improved synthetic method for coumarins.
5
6
COOEt
CHO
OH
6
5
∆
Ph3P=CHCOOEt (3)
R
R
R
R
COOEt
OH
Et2NPh
7
OH
4
O
O
8
3
2
E-4
Z-4
1
Scheme 1
We attempted Z-olefination (the Ando-HWE reaction)2 of 2, which is known as the Z-selective Horner-
Wadsworth-Emmons (HWE) reaction (Table 1). Treatment of salicylaldehyde (2a) with ethyl
diphenylphosphonoacetate (5a) at 0°C in the presence of NaI gave an unexpected intramolecular
† Dedicated to Professor Yuichi Kanaoka for the celebration of his 75th birthday.

phosphonate derivative (6a) in 33% yield along with the E-olefinated product (E-4a) in 37% yield. An
increase in the selectivity for 6a (61% yield) versus E-4a (12% yield) was observed when the reaction
was conducted at low temperatures (-78°C). Of the additive salts (NaI, LiCl, KI, or MgBr2), the addition
of NaI afforded the highest selectivity for 6a (Table 1).
Table 1. Reaction of Salicylaldehyde with (PhO)2P(O)CH2COOEt (5a).
COOEt
OPh
O
COOEt
CHO
(PhO)2P(O)CH2COOEt (5a)
+
P
DBU, salt
O
OH
OH
2a
6a
E-4a
Product (Yield, %)
Temp (°C )
Time (h)
Salt
6a
E-4a
0
-78
-78
-78
-78
1.5
2.0
33
61
26
36
15
37
12
53
33
29
NaI
NaI
7.0
LiCl
KI
3.0
12.8
MgBr2
O
P
COOEt
RO
RO
HWE
O
reaction
O
O
1a
HO
OR
HO
RO
cis-10
COOEt
OH
Knoevenagel
reaction
(EtO) P(O)
2
COOEt
P
P(O)(OEt)
2
O
H
O
O
O
E-9
(RO)2P(O)CH2COOEt
8
OH
O
erythro-7
EtOOC
5a,b
O
a : R = Ph
b : R = Et
P
RO
RO
trans-11
+
OH
2a
COOEt
OR
EtOOC
O
P
P
O
O
RO
RO
O
6a,b
cis-11
OR
RO
COOEt
O
P
O
(EtO) P(O)
COOEt
H
2
OH
Knoevenagel
reaction
OH
Z-9
threo-7
O
P
COOEt
RO
RO
HWE
E-4a
O
reaction
HO
trans-10
Scheme 2

A mechanistic study of the HWE reaction reported that the trans 4-membered oxaphosphetane
intermediate (trans-10) was more stable than the cis intermediate (cis-10), but that the erythro-aldol
adduct (erythro-7) was more stable than threo-7 (Scheme 2).3 We postulated that 6a might be formed via
another intermediate of coumarin (1a) from erythro-7. Namely, the six-membered phosphonate (trans-
11 ) is an intermediate in the production of 6a from erythro-7, and the occurring dehydration of trans-11
is a transforms 6a, while threo-7 gives E-4a via the stable intermediate, trans-10.
N. A. Rodios and co-workers4 reported that the Knoevenagel reaction of 2a with ethyl
diethylphosphonoacetate (5b) afforded 6b via Z-olefin (Z-9) from the threo-aldol adduct (threo-7) and
coumarin-7-phosphonate (8) via E-olefin (E-9) from erythro-7 (Scheme 2). Of the differences in the
conditions of the HWE and Knoevenagel reactions, we focused on which base to use in the reaction of 2a
with 5b in the presence of NaI/DBU under refluxing toluene (Scheme 3). This reaction afforded neither
6b nor 8, but E-4a in 26% yield, along with the ethylated product (12) of E-4a in 22% yield. The
production of 12 was confirmed by heating E-4a with 5b. Consequently, we understood that the reaction
of 2 with 5 in the presence of NaI/DBU runs not via the Knoevenagel reaction, but via the HWE reaction,
and that the intermediate in the transformation of 6a or 6b is erythro-7.
piperidine
+
+
8
(70%)
6b
(9%)
toluene, reflux
+
2a
5b
COOEt
NaI / DBU
E-4a
OEt
toluene, reflux
(26%)
12 (22%)
5b, toluene, reflux. 53%
Scheme 3
A new synthetic method for 1 was developed using the acetate of 2 (Table 2, Method B). Successive
acetylation of 2, Ando-HWE reaction, and hydrolysis afforded 1 and E-4 without a high reaction
temperature. In comparison with Method A, this method was adopted for the synthesis of 1 with
substituents at the 8 position, and should be very useful for the synthesis of 1b,d,e,f. While the selectivity
for 1 and E-4 was high in most of the reaction, the selectivity for 1j,k and E-4j,k produced from 2 with
an electron-withdrawing group (COOMe, NO2) at the 5 position decreased.

Table 2. A synthetic method of coumarin (1).
5
Method A
6
Ph3P=CHCOOEt
R
6
3
7
O
O
Et2NPh, reflux
CHO
OH
5
8
6
1
+
R
4
1) Ac2O, DMAP, THF, rt, 1-3 h
COOEt
5
2
R
2) (PhO)2P(O)CH2COOEt, DBU, NaI,
4
OH
Method B
3
THF, -78℃, 1-2 h
3) KOH, MeOH, H2O, 15 min
E-4
Product (yield, %)
Product (yield, %)
R
H
R
Run
Method
1
E-4
Run
Method
1
E-4
1
2
A
B
89 (1a)
72 (1a)
-
1 (4a)a
)
a)
45 (1b)a
-
)
13
14
3
4
A
B
A
B
70 (
83 (
)
-
1g
5-OH
3-OH
3-OMe
3-Br
4 (4g)f)
83 (1b) 4 (4b)b)
1g
)
a)
81 (1c)a) 11 (4c)a)
78 (1c) 10 (4c)
15
16
5
6
A
B
A
B
93 (
62 (
)
)
-
1h
5-OMe
5-Br
4 (4h)g)
1h
59 (1d)c)
97 (1d)
-
-
17
18
7
8
A
B
A
B
65 ( )c)
-
1i
9 (4i)
84 (1i)
77 (1j)c
)
19
20
9
A
B
A
B
-
-
22 (4e)
5-COOMe
5-NO2
3-COOMe
3-NO2
10
12 (4j)h)
39 (1j)
85 (1e)
-
28 (1k)e
21 (1k)
)
21
22
11
12
A
Bd)
A
B
-
10 (1f)
49 (1f)e)
-
-
64 (4k)e)
a) Ref. 1a. b) Ref. 7. c) Ref. 1b. d) Acetate of 2f
was isolated. e) Ref. 1c.
f) Ref. 6. g) Ref. 8. h) Bis(methoxycarbonyl) compound
was obtained.
EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. IR
spectra were recorded on a JASCO A-102 spectrophotometer. MS spectra were recorded on a VG-70SE
1
spectrometer. H-NMR spectra were run on a JASCO MY 60FT or a Varian VXR-200 spectrometer.
Analytical HPLC was performed with Chemcosorb 5Si-U (Chemco). Merck silica gel 60 (230-400 mesh)
was employed for column chromatography. Extracts were dried over anhydrous MgSO4.
Reaction of salicylaldehyde (2a) with ethyl diphenylphosphonoacetate (5a)
Sodium iodide
(0.36 g, 2.4 mmol) and DBU (0.32 mL, 2.2 mmol) were added at 0°C to a solution of 5a (0.64 g,
2.0 mmol) in dry THF (20 mL) and the mixture was stirred at the same temperature for 10 min. After

cooling at -78°C, 2a (0.24 mL, 2.2 mmol) was added to the mixture and the mixture was stirred at the
same temperature for 2 h. The mixture was acidified by 10% aqueous HCl solution and extracted with
AcOEt (80 mL). The organic layer was washed with brine (80 mL), dried and the solvent was removed
in vacuo. The residue was subjected to column chromatography (SiO2, AcOEt:hexane = 1:5). The first
eluant gave ethyl (E)-3-(2-hydroxyphenyl)propenate (E-4a, 0.048 g, 12%) as colorless plates, mp 83—
86°C (hexane and ether, lit.,1a 84—86°C). The second eluant gave ethyl 2-oxo-2-phenoxy-2H-
benzo[e][1,2]oxaphosphine-3-carboxylate (6a, 0.400 g, 61%) as colorless plates, mp 66—69°C. IR
-1
1
(KBr) cm : 1720. H-NMR (200 MHz, CDCl ) δ: 1.29 (t, 3H, J = 7.1 Hz), 4.35 (qd, 2H, J = 7.1, 2.5
3
Hz), 6.80—7.53 (m, 9H), 8.32 (d, 1H, J = 38.4 Hz). Anal. Calcd for C H O P: C, 61.82; H, 4.58.
17 15 5
+
+
Found: C, 62.00; H, 4.74. FAB–MS (positive ion mode) m/z: 331 (M+1) , 285 (M -OC2H5).
The reaction of 2a with 5a using other inorganic salt (LiCl, KI, MgBr2) was treated by the same method
as the above described method to afford the results in Table 1.
Reaction of salicylaldehyde (2a) with ethyl diethylphosphonoacetate (5b) Sodium iodide (0.36 g,
2.4 mmol) and DBU (0.32 mL, 2.2 mmol) were added at 0°C to a solution of 5b (0.45 g, 2.0 mmol) in
dry toluene (6 mL). After stirring for 10 min, 2a (0.24 mL, 2.2 mmol) was added to the mixture and the
mixture was stirred at reflux for 6 h. The mixture was acidified by 10% aqueous HCl solution and
extracted with AcOEt (80 mL). The organic layer was washed with saturated aqueous NaHCO3 solution
(60 mL) and brine (80 mL), dried and the solvent was removed in vacuo. The residue was subjected to
column chromatography (SiO2, AcOEt:hexane = 1:4). The first eluant gave a mixture (0.168 g) of 2a and
ethyl (E)-3-(2-ethoxyphenyl)propionate (12). The second eluant gave E-4a (0.0996 g, 26%). A mixture of
2a and 12 was subjected to re-column chromatography (SiO2, hexane) to give 12 (0.0962 g, 22%) as
1
5
1
colorless oil, whose H-NMR spectral data were agreed with reported one . H-NMR (60 MHz, CDCl )
3
δ: 1.33 (t, 3H, J = 7.3 Hz), 1.45 (t, 3H, J = 7.3 Hz), 4.01 (q, 2H, J = 7.3 Hz), 4.26 (q, 2H, J = 7.3 Hz),
6.53 (d, 1H, J = 17.2 Hz), 6.81—7.56 (m, 4H), 8.03 (d, 1H, J = 17.2 Hz).
Reaction of ethyl (E)-3-(2-hydroxyphenyl)propenoate (E-4a) with ethyl diethylphosphonoacetate
(5b) Sodium iodide (0.36 g, 2.4 mmol) and DBU (0.32 mL, 2.2 mmol) were added at 0°C to a solution
of 5b (0.22 g, 1.0 mmol) in dry toluene (6 mL). After stirring for 10 min, E-4a (0.211 g, 1.1 mmol) was
added to the mixture and the mixture was stirred at reflux for 4 h. The solvent was removed in vacuo. The
residue was subjected to column chromatography (SiO2, AcOEt:hexane=1:4). The first eluant gave 12

(0.128 g, 53%). The second eluant gave E-4a (0.100 g, 47%).
8-Hydroxycoumarin (1b) Acetic anhydride (0.40 mL, 4.2 mmol) and DMAP (0.513 g, 4.2 mmol)
were added at 0°C for 5 min to a solution of 2,3-dihydroxybenzaldehyde (0.276 g, 2.0 mmol) in dry THF
(2 mL). The mixture was stirred at rt for 2 h. A phosphonoacetate solution, which was prepared by
stirring a mixture of NaI (0.564 g, 3.1 mmol), DBU (0.46 mL, 3.1 mmol), and 5a (0.897 g, 2.8 mmol) in
dry THF (18 mL) at 0°C for 10 min, was added at -78°C for 3 h to the mixture. Potassium hydroxide
(0.56 g, 10.0 mmol) in MeOH/H2O (3:1, 2.0 mL) was added to the mixture. After stirring for 15 min, the
mixture was acidified with 10% aqueous HCl solution and extracted with AcOEt (90 mL). The organic
layer was washed with brine (110 mL), dried and the solvent was removed in vacuo. The residue was
subjected to column chromatography (SiO2, AcOEt:hexane = 1:7). The first eluant gave starting material
(0.021 g, 8%). The second eluant gave 1b (0.270 g, 83%) as light yellow needles, mp 161—162°C
(AcOEt and hexane, lit.,1a 152—156°C). The second eluant gave ethyl (E)-3-(2,3-
dihydroxyoxyphenyl)propenate (E-4b, 0.016 g, 4%) as colorless needles, mp 143—145°C (ether and
hexane, lit.,7 137—139°C).
8-Bromocoumarin (1d)
Acetic anhydride (0.20 mL, 2.1 mmol) and DMAP (0.257 g, 2.1 mmol) were
added at 0°C for 5 min to a solution of methyl 3-bromo-2-hydroxybenzaldehyde (0.402 g, 2.0 mmol) in
dry THF (2 mL). The mixture was stirred at rt for 40 min. A phosphonoacetate solution, which was
prepared by stirring a mixture of NaI (0.414 g, 2.8 mmol), DBU (0.38 mL, 2.5 mmol), and 5a (0.737 g,
2.3 mmol) in dry THF (18 mL) at 0°C for 10 min, was added at -78°C for 1 h to the mixture. Potassium
hydroxide (0.56 g, 10.0 mmol) in MeOH/H2O (3:1, 2.0 mL) was added to the mixture. The mixture was
stirred at rt for 15 min. The mixture was acidified with 10% aqueous HCl solution and extracted with
AcOEt (100 mL). The organic layer was washed with brine (40 mL), dried and the solvent was removed
in vacuo. The residue was subjected to column chromatography (SiO2, hexane) to give 1d (0.43 g, 97%)
as yellow needles, mp 135—136°C (MeOH, lit.,1b 136.5—137°C).
8-Methoxycarbonylcoumarin (1e) Acetic anhydride (0.20 mL, 2.1 mmol) and DMAP (0.257 g,
2.1 mmol) were added at 0°C for 5 min to a solution of methyl 3-formyl-2-hydroxybenzoate (0.360 g,
2.0 mmol) in dry THF (2 mL). The mixture was stirred at rt for 1.5 h. A phosphonoacetate solution,
which was prepared by stirring a mixture of NaI (0.414 g, 2.8 mmol), DBU (0.38 mL, 2.5 mL), and 5a
(0.737 g, 2.3 mmol) in dry THF (22 mL) at 0°C for 10 min, was added at -78°C for 1 h to the mixture.
Potassium hydroxide (0.56 g, 10.0 mmol) in MeOH/H2O (3:1, 2.0 mL) was added to the mixture. The

mixture was stirred at rt for 20 min. The mixture was acidified with 10% aqueous HCl solution and
extracted with AcOEt (80 mL). The organic layer was washed with brine (90 mL), dried and the solvent
was removed in vacuo. The residue was subjected to column chromatography (SiO2, AcOEt:hexane =
1:6) to give 1e (0.349 g, 86%) as colorless needles, mp 164.5—165.5°C (AcOEt and hexane). IR (KBr)
-1
1
cm : 1710, 1730. H-NMR (60 MHz, CDCl ) δ: 4.01 (s, 3H), 6.47 (d, 1H, J = 9.8 Hz), 7.31—8.00 (m,
3
4H). Anal. Calcd for C H O : C, 64.71; H, 3.95. Found: C, 64.52; H, 4.09. FAB–MS (positive ion
11 8 4
+
mode) m/z: 205 (M+1) .
8-Nitrocoumarin (1f) Acetic anhydride (0.23 mL, 2.4 mmol) was added at 0°C for 5 min to a solution
dissolved 2-hydroxy-3-nitrobenzaldehyde (0.167 g, 1.0 mmol) in dry pyridine (1 mL). The mixture was
stirred at rt for 1 h. The reaction mixture was poured into 10% aqueous HCl solution (40 mL), and
extracted with AcOEt (50 mL). The organic layer washed with saturated aqueous NaHCO3 solution
(40 mL) and brine (40 mL), dried, and the solvent was removed in vacuo. The residue was recrystallized
from a mixture of ether and hexane to give 2-acetoxy-3-nitrobenzaldehyde (0.123 g, 59%) as yellow
-1
1
needles, mp 89—90°C. IR (KBr) cm : 1715, 1770. H-NMR (60 MHz, CDCl ) δ: 2.49 (s, 3H), 7.58—
3
7.71 (m, 1H), 8.15—8.28 (m, 2H), 10.23 (s, 1H). Anal. Calcd for C H NO : C, 51.68; H, 3.37. Found: C,
9 7
5
51.51; H, 3.53.
A phosphonoacetate solution, which was prepared by stirring a mixture of NaI (0.200 g, 1.3 mmol), DBU
(0.18 mL, 1.2 mL), and 5a (0.35 g, 1.1 mmol) in dry THF (10 mL) at 0°C for 10 min, 2-acetoxy-3-
nitrobenzaldehyde (0.21 g, 1.0 mmol) was added at -78°C for 1 h to the mixture. The mixture was
neutralized with saturated aqueous NH4Cl solution and extracted with AcOEt (90 mL). The organic layer
was washed with brine (80 mL), dried, and the solvent was removed in vacuo. The mixture of the residue
and K2CO3 (1.50 g, 10.9 mml) in EtOH/H2O (1:1, 20ml) was stirred at rt for 21 h. The mixture was
acidified with 10% aqueous HCl solution and extracted with AcOEt (80 mL). The organic layer was
washed with brine (80 mL), dried and the solvent was removed in vacuo. Recrystallization (CHCl3 and
hexane) gave 1f (0.159 g, 49% based on 2-hydroxy-3-nitrobenzaldehyde) as yellow needles, mp 190—
191°C (CHCl3 and hexane, lit.,1c 190—191°C).
The reaction of 2a,c,g,h,i,j,k with 5a was carried out by the same method as the preparation of 1d to
afford the results in Table 2. The following are the physicochemical properties of new compounds ((E)-
4i,j) and 1H-NMR spectral data of other compounds were agreed with the reported one.

Ethyl (E)-3-(5-bromo-2-hydroxyphenyl)propenoate (4i)
colorless needles, mp 122.5—123.5°C
-1
1
(ether and hexane). IR (KBr) cm : 1685. H-NMR (60 MHz, CDCl ) δ: 1.35 (t, 3H, J = 7.3 Hz), 4.30
3
(q, 2H, J = 7.3 Hz), 6.62 (d, 1H, J = 15.9 Hz), 6.83—7.60 (m, 3H), 7.98 (d, 1H, J = 15.9 Hz). Anal.
Calcd for C H O Br: C, 48.73; H, 4.09. Found: C, 48.48; H, 4.23. FAB–MS (positive ion mode) m/z:
11 11 3
+
272 (M+1) .
Methyl (E)-3-(2-hydroxy-5-methoxycarbonylphenyl)propenoate (4j)
colorless needles, mp 150—
-1
1
154°C (ether and hexane). IR (KBr) cm : 1690, 1725. H-NMR (60 MHz, CDCl ) δ: 3.84 (s, 3H), 3.90
3
(s, 3H), 6.71 (d, 1H, J = 15.9 Hz), 6.95 (d, 1H, J = 7.8 Hz), 7.93 (dd, 1H, J = 7.8, 2.3 Hz), 8.06 (d, 1H, J
= 15.9 Hz), 8.20 (d, 1H, J = 2.3 Hz). Anal. Calcd for C H O : C, 61.02; H, 5.12. Found: C, 60.99; H,
12 12 5
+
5.23. FAB–MS (positive ion mode) m/z: 237 (M+1) .
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