An efficient and versatile synthesis of isoflavones from 2-methoxybenzoic acids

Full text of DOI:10.1002/bkcs.10806

Note
DOI: 10.1002/bkcs.10806
BULLETIN OF THE
J. I. Lee
KOREAN CHEMICAL SOCIETY
An Efficient and Versatile Synthesis of Isoflavones from
2-Methoxybenzoic Acids
*
Jae In Lee
Department of Chemistry, College of Natural Science, Duksung Women’s University, Seoul 132-714,
Korea. *E-mail: jilee@duksung.ac.kr
Received January 28, 2016, Accepted April 2, 2016, Published online June 26, 2016
Keywords: Isoflavones, Acyl substitution, Demethylation, Formylation
Isoflavones (3-aryl-4H-1-benzopyran-4-ones) are found nat-
urally in soybeans and many plants of the Leguminosae
family.1 They have attracted much attention due to their
biological activities, such as their anti-cancer,2 anti-
inflammatory,3 and antifungal properties.4 Isoflavones
intake through foods is important to human health, because
they potentially regulate fatty acid metabolism5 and
methoxy-substituted isoflavones in particular increase cell
permeability.2b
Isoflavones have been generally synthesized via 2-
hydroxydeoxybenzoin or 20-hydroxychalcone intermedia-
tes.6 The 2-hydroxydeoxybenzoins were prepared by the elec-
trophilic substitution of phenols with phenylacetic acids7 and
benzyl cyanides8 in the presence of BF3ꢀEt2O and ZnCl2/
HCl, respectively, using heating. The methylene group of the
resulting 2-hydroxydeoxybenzoins were formylated with N-
formyl imidazole,9 acetic formic anhydride,10 DMF dimethyl
acetal,11 PCl57a or CH3SO2Cl7b,c,8 in DMF. These intermedi-
ates were followed by ring closure to provide the correspond-
ing isoflavanones, which were then converted into
isoflavones under acidic heating conditions. The treatment of
20-hydroxychalcones, prepared by the condensation of 20-
hydroxyacetophenones and benzaldehydes using KOH, with
thallium(III) nitrate12 or phenyliodine diacetate13 in trimethyl
orthoformate provided the corresponding dimethyl acetals.
The dimethyl acetals underwent 1,2-aryl shift and subsequent
elimination of CH3OH to provide isoflavones.
at 150ꢁC, with o-iodoxybenzoic acid formed isoflavones in
moderate yields.17
Although several methods have been developed for the
synthesis of isoflavones, some have disadvantages, includ-
ing multiple steps, vigorous conditions, low yields, and
tedious separations. Furthermore, the synthesis of 2-hydro-
xydeoxybenzoins by electrophilic substitution was effective
only for the symmetrical phenol derivatives. In this study,
we developed an efficient and versatile method for the syn-
thesis of isoflavones from 2-methoxybenzoic acids under
mild conditions.
N-Methoxy-N-methyl 2-methoxybenzamides (2a–2e, 2g)
were readily prepared by treating 2-methoxybenzoic acids
(1a–1e, 1g) with N-methoxy-N-methylcarbamoyl chloride
and triethylamine (Scheme 1). The addition of 0.05 equiv of
4-(dimethylamino)pyridine (4-DMAP) accelerated the rate
of conversion of carboxylic-carbamic anhydride intermedi-
ates to 2a–2e and 2g in acetonitrile. The reaction was com-
pleted within 2 h at room temperature and 2a–2e/2g were
obtained in 79–91% yields after the usual basic work-up
(2a: 84%, 2b: 83%, 2c: 91%, 2d: 79%, 2e: 83%, 2g: 85%).
The synthesis of 1-(2-methoxyphenyl)-2-phenylethanones
(4) was carried out by the acyl substitution of 2 with benzyl-
magnesium chlorides (3h–3n) in THF. The reaction pro-
ceeded smoothly for 0.5 h at 0ꢁC, regardless of the kind of
electron-withdrawing and electron-donating substituents in
both phenyl rings, and 4 was obtained in 78–93% yields
after the usual acidic work-up (4ah: 81%, 4ai: 93%, 4bj:
83%, 4bk: 82%, 4cl: 92%, 4cm: 91%, 4dm: 80%, 4dn:
78%, 4ej: 83%, 4gh: 88%). However, an attempt to prepare
1-(2,6-dimethoxyphenyl)-2-phenylethanone (4fh) by the
reaction of N-methoxy-N-methyl 2,6-dimethoxybenzamide
(2f) and benzylmagnesium chloride was not successful,
probably due to the steric effects of the two 2,6-
dimethoxy groups. 2f was prepared by the acyl substitu-
tion of 2,6-dimethoxybenzoyl chloride with N,O-
dimethylhydroxylamine hydrochlide in the presence of 2
equiv of triethylamine in 91% yield. Therefore, 4fh was
prepared by the acyl substitution of 2,6-dimethoxybenzoyl
chloride with benzylmagnesium chloride pretreated with
copper(I) cyanide, in THF for 1 h between 0ꢁC and room
temperature in 78% yield.
Isoflavones have also been synthesized by the coupling
of 3-iodochromones with arylboronic acids. The condensa-
tion of 20-hydroxyacetophenones with DMF dimethyl acetal
formed
3-(dimethylamino)-20-hydroxyphenylpropenones,
which were cyclized using iodine to form 3-iodochro-
mones. This process was followed by Suzuki coupling with
arylboronic acids or aryl boronates to obtain isoflavones.14
3-Iodochromones were also coupled with triarylbismuths
under catalytic palladium to form isoflavones.15 Further-
more, the metalation of chromones with 2,2,6,6-tetramethyl
piperidyl zinc chloride led to the C3-zincated intermediates,
which were coupled with p-iodoanisole under palladium
catalyst to form isoflavones.16 Alternatively, the oxidation
of isoflavanones, which were prepared from the gold(I)-
catalyzed annulation of salicylaldehydes and arylacetylenes
Bull. Korean Chem. Soc. 2016, Vol. 37, 1132–1135
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KOREAN CHEMICAL SOCIETY
R5
R8
R6
R7
MgCl
3h-n
R1
1)
R1
R1
R4
R2
R3
OMe
R5
R2
R3
OMe
OH
R2
R3
OMe
N
R6
b
a
2) H3O+
OMe
R4
O
R7
Me
R4
O
O
R8
1a-g
2a-g
4
R1=R2=R3=R4=H (a); R1=OMe, R2=R3=R4=H (b);
R5=R6=R7=R8=H (h); R5=OMe, R6=R7=R8=H (i);
R6=Br, R5=R7=R8=H (j); R6=OMe, R5=R7=R8=H (k);
R7=Me, R5=R6=R8=H (l); R7=OMe, R5=R6=R8=H (m);
R6=R8=OMe, R5=R7=H (n)
R2=OMe, R1=R3=R4=H (c); R3=Cl, R1=R2=R4=H (d);
R3=OMe, R1=R2=R4=H (e); R4=OMe, R1=R2=R3=H (f);
R2=R3=OMe, R1=R4=H (g)
R1
R1
R2
R3
OH
R2
R3
O
O
R5
R5
B
A
1)
2)
d
e
c
f
R6
R7
R6
R7
R4
O
R4
R8
R8
5
6
Scheme 1. Reagents and conditions: (a) ClCONMe(OMe), Et3N, 0.05 equiv 4-DMAP, CH3CN, rt, 2 h; (b) THF, 0ꢁC, 0.5 h, CuCN for
4fh; (c) 1 equiv BBr3, CH2Cl2, approximately −20ꢁC–rt, 1 h; (d) approximately 3–5 equiv BF3ꢀEt2O, THF, approximately 0ꢁC–rt, 0.5 h;
(e) 2 equiv DMF-POCl3, THF, rt, approximately 2–6 h; (f ) 0.1 N HCl, rt, 1 h.
Selective demethylation of the 2-methoxy group in 4 was
successfully accomplished using boron tribromide. The
addition of 1 equiv of boron tribromide to a solution of 4 in
methylene chloride at −20ꢁC seemed to produce 6-
membered chelates between the oxygen atoms of the 2-
methoxy/carbonyl group and boron atom. Subsequent dis-
placement of the methyl group by the attack of the bromide
anion produced the corresponding alkoxy borates, which
were hydrolyzed with H2O to produce 5 in 67–93% yields
(5ah: 87%, 5ai: 91%, 5bj: 90%, 5bk: 89%, 5cl: 77%, 5cm:
74%, 5dm: 67%, 5dn: 70%, 5ej: 81%, 5fh: 93%, 5gh:
85%). In particular, only one methoxy group of 4fh was
selectively demethylated with 1 equiv of boron tribromide
at −20ꢁC to produce 1-(2-hydroxy-6-methoxyphenyl)-2-
phenylethanone (5fh) in 93% yield.
The synthesis of isoflavones (6) from 5 was based on the
formylation of the methylene group of 5 using DMF-
POCl3. Previously, the reaction of the DMF-POCl3 com-
plex on benzyl 2-hydroxyphenyl ketones led to isoflavones,
for which DMF was used as the reagent and solvent for
18 h at gentle reflux.18 However, few examples have been
reported and thus the scope of the reaction was not fully
investigated. Furthermore, 6-methoxy-substituted 2-
hydroxyphenyl benzyl ketone failed to produce 5-methoxy-
substituted isoflavone by treatment with DMF-POCl3 under
various conditions. Our methods circumvented these disad-
vantages using BF3ꢀEt2O as Lewis acid and THF as the sol-
vent under mild conditions.
room temperature. The reaction proceeded smoothly with
the substitution on N,N-dimethyl(chloromethylene)-
ammonium salt by boron enolate of 5 and subsequent ring
closure. After stirring for 2–6 h at room temperature, the
resulting tan solution was treated with 0.1 N HCl solution
and further stirring for 1 h led to the elimination of the
dimethylamino group to produce isoflavones (6) in 78–94%
yields after the usual acidic work-up. Thus, the synthesis of
6 from 5 was carried out successfully in the one pot opera-
tion of substitution, cyclization, and elimination. The use of
POCl3 for the formylation of 5 has solubility advantage
over those of SOCl2 and (COCl)2, for which the corre-
sponding N,N-dimethyl(chloromethylene)ammonium salt
was not soluble in THF.
As shown in Table 1, various isoflavones were synthe-
sized from 2-methoxybenzoic acids in overall high yields.
The acyl substitution of 2 with 3 proceeded regardless of
the position of the methoxy or halo (bromo, chloro)
groups in 2 and 3. In addition, the selective demethylation
of 2-methoxy group in 4 was not affected by these groups
with 1 equiv of boron tribromide. The ring closure of
5 based on the formylation using DMF-POCl3 proceeded
well with both the electron-donating groups (6bj, 6bk,
6cl, 6cm, 6ej, 6gh) and the electron-withdrawing groups
(6dm, 6dn) of the A-ring. The ring closure also proceeded
with both the electron-donating groups (6ai, 6bk, 6cl,
6cm, 6dm, 6dn) and the electron-withdrawing groups
(6bj, 6ej) of the B-ring under the same conditions. In par-
ticular, the reaction of 4fh pretreated with BF3ꢀEt2O using
DMF-POCl3 proceeded smoothly for 3 h at room tempera-
ture to produce 5-methoxyisoflavone (6fh) regardless of
the steric hindrance of the o-methoxy group in 5fh in
85% yield.
The treatment of DMF with POCl3 in THF for 0.5 h
between 0ꢁC and room temperature produced a pale pink
colored solution. The resulting N,N-dimethyl(chlorometh-
ylene)ammonium salt was added to the solution of 5 pre-
treated with BF3ꢀEt2O in THF for 0.5 h between 0ꢁC and
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KOREAN CHEMICAL SOCIETY
Table 1. Synthesis of isoflavones 6 from 5.
Entry 6 Chemical name
R1
R2
R3
R4
R5
R6
R7
R8
Isolated yields, %a
ah
ai
bj
bk
cl
cm
dm
dn
ej
Isoflavone
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
Cl
Cl
OMe
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
Br
OMe
H
H
H
OMe
Br
H
H
H
H
H
Me
OMe
OMe
H
H
H
H
H
H
H
H
H
H
80 (47)
84 (60)
81 (50)
85 (51)
82 (53)
81 (50)
81 (34)
20-Methoxyisoflavone
30-Bromo-8-methoxyisoflavone
30,8-Dimethoxyisoflavone
7-Methoxy-40-methylisoflavone
40,7-Dimethoxyisoflavone
6-Chloro-40-methoxyisoflavone
6-Chloro-30,50-dimethoxyisoflavone
30-Bromo-6-methoxyisoflavone
5-Methoxyisoflavone
OMe 83 (36)
H
OMe
H
H
H
H
78 (44)
85 (62)b
94 (60)
fh
gh
a
H
H
H
H
H
6,7-Dimethoxyisoflavone
OMe OMe
H
H
The numbers in parentheses indicate the overall yields from 2-methoxybenzoic acids 1.
b
The number in parenthesis indicates the overall yields from 2,6-dimethoxybenzoyl chloride.
Experimental
Preparation of 1-(2-hydroxyphenyl)-2-(2-methoxyphe-
nyl)ethanone (5ai). Boron tribromide (1.0 M in CH2Cl2,
3.2 mL, 3.2 mmol) was slowly added to a solution of 4ai
(820 mg, 3.2 mmol) in methylene chloride (12 mL) at
−20ꢁC. The mixture was stirred for 1 h between −20ꢁC and
room temperature and then quenched with H2O (2 mL). The
mixture was poured into a saturated NaHCO3 solution
(30 mL) and extracted with methylene chloride
(3 × 20 mL). The condensed residue was purified with sil-
ica gel column chromatography using 20% EtOAc/n-hexane
Preparation of N-methoxy-N-methyl 2-methoxybenz-
amide (2). 2-Methoxybenzoic acid (1a, 761 mg,
5.0 mmol), triethylamine (725 μL, 5.2 mmol), and 4-
DMAP (61 mg, 0.5 mmol) was added to a solution of N-
methoxy-N-methyl carbamoyl chloride (619 mg, 5.0 mmol)
in acetonitrile at room temperature and stirred for 1.5 h.
After evaporation of acetonitrile, the mixture was poured
into saturated NaHCO3 solution (40 mL) and extracted with
methylene chloride (3 × 25 mL). The condensed residue
was purified with short pathway silica gel column chroma-
tography using 50% EtOAc/n-hexane to give 2a (820 mg,
1
to give 5ai (706 mg, 91%). H NMR (300 MHz, CDCl3) δ
12.24 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.43–7.49 (m,
1H), 7.25–7.32 (m, 1H), 7.18 (dd, J = 7.4, 1.6 Hz, 1H),
6.94–7.00 (m, 2H), 6.87–6.93 (m, 2H), 4.31 (s, 2H), 3.79 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 204.2, 162.6, 157.2,
136.2, 131.0, 130.3, 128.7, 123.0, 120.7, 119.4, 118.8,
118.5, 110.7, 55.4, 39.6; FT-IR (film) 3436 (OH), 1642
(C O) cm−1; MS m/z (%) 242 (M+, 26), 241 (100).
1
84%). H NMR (300 MHz, CDCl3) δ 7.33–7.39 (m, 1H),
7.24–7.28 (m, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.91 (d,
J = 6.4 Hz, 1H), 3.85 (s, 3H), 3.49 (s, 3H), 3.32 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 177.2, 155.8, 130.6, 127.7,
125.3, 120.5, 111.2, 61.0, 55.7 (overlapped); FT-IR (film)
1640 (C O) cm−1; MS m/z (%) 195 (M+, 2), 135 (100).
Preparation of 20-methoxyisoflavone (6ai). BF3ꢀEt2O
(1.2 mL, 9.7 mmol) was added to a solution of 5ai (582 mg,
2.4 mmol) in THF (6 mL) at 0ꢁC and stirred for 0.5 h
between 0ꢁC and room temperature. Phosphorus(V) oxy-
chloride (447 μL, 4.8 mmol) was added to another flask con-
taining DMF (351 mg, 4.8 mmol) in THF (6 mL) at 0ꢁC and
stirred for 0.5 h between 0ꢁC and room temperature. The
resulting pale pink colored solution containing N,N-dimethyl
(chloromethylene)ammonium salt was added to the above
reaction mixture at room temperature. After being stirred for
6 h, 0.1 N HCl solution (25 mL) was added to the mixture
and was stirred further for 1 h. The solvent was removed in
vacuo, then the mixture was poured into a 0.1 N HCl solution
(25 mL), and extracted with methylene chloride
(3 × 20 mL). The condensed residue was purified by recrys-
tallization in 10% EtOAc/n-hexane twice to give 6ai
(509 mg, 84%). Mp 184–186ꢁC; 1H NMR (300 MHz,
CDCl3) δ 8.29 (dd, J = 8.0, 1.4 Hz, 1H), 8.00 (s, 1H),
7.65–7.71 (m, 1H), 7.48 (dd, J = 8.4, 0.6 Hz, 1H), 7.31–7.45
(m, 3H), 7.03 (dd, J = 7.4, 1.0 Hz, 1H), 6.97–7.01 (m, 1H),
3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 157.5,
Preparation of 1-(2-methoxyphenyl)-2-(2-methoxyphe-
nyl)ethanone (4ai). 2-Methoxybenzylmagnesium chloride
(3i, 0.25 M in THF, 16 mL, 4.0 mmol) was added to a
solution of 2a (742 mg, 3.8 mmol) in THF (6 mL) at 0ꢁC.
The mixture was stirred for 0.5 h between 0ꢁC and room
temperature and then quenched with a 0.1 N HCl solution
(5 mL). After the evaporation of THF, the mixture was
poured into a 0.1 N HCl solution (40 mL) and extracted
with methylene chloride (3 × 20 mL). The condensed resi-
due was purified with silica gel column chromatography
1
using 20% EtOAc/n-hexane to give 4ai (906 mg, 93%). H
NMR (300 MHz, CDCl3) δ 7.71 (dd, J = 7.7, 1.8 Hz, 1H),
7.42–7.48 (m, 1H), 7.22–7.30 (m, 1H), 7.18 (dd, J = 7.4,
1.5 Hz, 1H), 7.02 (dd, J = 7.5, 0.9 Hz, 1H), 6.91–6.99 (m,
2H), 6.86 (d, J = 8.2 Hz, 1H), 4.28 (s, 2H), 3.92 (s, 3H),
3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.4, 158.3,
157.6, 132.9, 131.2, 130.3, 128.9, 128.1, 124.7, 120.5,
120.4, 111.4, 110.4, 55.5, 55.3, 45.4; FT-IR (film) 1675
(C O) cm−1; MS m/z (%) 256 (M+, 20), 135 (100).
Bull. Korean Chem. Soc. 2016, Vol. 37, 1132–1135
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BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
156.3, 154.2, 133.3, 131.7, 129.7, 126.3, 125.0, 124.6, 122.7,
120.9, 120.5, 118.0, 111.3, 55.7; FT-IR (KBr) 1647 (C O)
cm−1; MS m/z (%) 252 (M+, 100).
Acknowledgments. This research was supported by the
Duksung
Women’s
University
Research
Grants
3000002480 (2015).
6ah, 6cm, 6dm, 6gh. Known compounds.2b,7a,15
30-Bromo-8-methoxyisoflavone (6bj). Mp 174–176ꢁC; H
1
References
NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.87 (dd, J = 8.1,
1.4 Hz, 1H), 7.75 (t, J = 1.7 Hz, 1H), 7.50–7.55 (m, 2H),
7.28–7.40 (m, 2H), 7.21 (dd, J = 8.0, 1.4 Hz, 1H), 4.03 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 175.7, 153.0, 148.7,
146.6, 133.8, 131.8, 131.3, 130.0, 127.6, 125.5, 125.2,
124.2, 122.5, 117.2, 114.4, 56.5; FT-IR (KBr) (C O)
1646 cm−1; MS m/z (%) 332 (M++2, 98), 330 (M+, 100).
30,8-Dimethoxyisoflavone (6bk). Mp 145–146ꢁC; 1H
NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.87 (dd, J = 8.1,
1.4 Hz, 1H), 7.32–7.38 (m, 2H), 7.16–7.21 (m, 2H), 7.12
(d, J = 7.6 Hz, 1H), 6.94 (dd, J = 8.3, 2.6 Hz, 1H), 4.02
(s, 3H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0,
159.6, 152.8, 148.7, 146.6, 133.1, 129.5, 125.6, 125.3,
124.9, 121.2, 117.3, 114.6, 114.2, 114.1, 56.4, 55.3; FT-IR
(KBr) 1645 (C O) cm−1; MS m/z (%) 282 (M+, 100).
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6.98 (dd, J = 8.9, 2.4 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H),
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6-Chloro-30,50-dimethoxyisoflavone
(6dn).
Mp
160–161ꢁC; 1H NMR (300 MHz, CDCl3) δ 8.26 (d,
J = 2.6 Hz, 1H), 8.03 (s, 1H), 7.62 (dd, J = 8.9, 2.4 Hz, 1H),
7.44 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 2.1 Hz, 2H), 6.50 (t,
J = 2.1 Hz, 1H), 3.82 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
174.9, 160.8, 154.4, 153.3, 133.8, 133.3, 131.3, 125.8, 125.5,
125.4, 119.8, 107.1, 100.7, 55.4; FT-IR (KBr) 1650 (C O)
cm−1; MS m/z (%) 318 (M++2, 30), 316 (M+, 100).
1
30-Bromo-6-methoxyisoflavone (6ej). Mp 134–136ꢁC; H
12. E. Kato, J. Kawabata, Bioorg. Med. Chem. Lett. 2010,
20, 4333.
NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.74 (t,
J = 1.7 Hz, 1H), 7.65 (d, J = 3.1 Hz, 1H), 7.49–7.54 (m,
2H), 7.43 (d, J = 9.1 Hz, 1H), 7.29–7.34 (m, 1H), 7.27
(dd, J = 4.7, 1.6 Hz, 1H), 3.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 175.6, 157.2, 153.1, 151.0, 134.1,
131.8, 131.1, 129.9, 127.6, 125.1, 123.9, 123.3, 122.5,
119.5, 105.5, 55.9; FT-IR (KBr) (C O) 1638 cm−1; MS m/
z (%) 332 (M++2, 96), 330 (M+, 100).
5-Methoxyisoflavone (6fh). Mp 89–90ꢁC; 1H NMR
(300 MHz, CDCl3) δ 7.84 (s, 1H), 7.49–7.56 (m, 3H),
7.33–7.42 (m, 3H), 7.00 (dd, J = 8.5, 0.9 Hz, 1H), 6.80 (d,
J = 8.3 Hz, 1H), 3.96 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 175.8, 160.4, 158.3, 151.0, 133.6, 132.0, 129.2, 128.2,
128.0, 126.5, 115.3, 110.0, 106.5, 56.4; FT-IR (KBr)
(C O) 1645 cm−1; MS m/z (%) 252 (M+, 100).
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(c) A. Ikedo, I. Hayakawa, T. Usui, S. Kazami, H. Osada,
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Bull. Korean Chem. Soc. 2016, Vol. 37, 1132–1135
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