A practical synthesis of a new series of isoflavanones

Article abstract of DOI:10.1016/j.cclet.2012.06.020

A practical six-step synthesis of 12 methylated and hydroxylated isoflavanones was accomplished starting from readily available m-xylene. A significant improvement of this procedure included application of the simple and commercially available reagents, avoidance of expensive reagents and catalysts, simple operations and excellent yields.

Full text of DOI:10.1016/j.cclet.2012.06.020

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 907–910
www.elsevier.com/locate/cclet
A practical synthesis of a new series of isoflavanones
*
Ju Na Liu, Shu Rong Ban, Hong Yu Xie, Qing Shan Li
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, China
Received 12 April 2012
Available online 4 July 2012
Abstract
A practical six-step synthesis of 12 methylated and hydroxylated isoflavanones was accomplished starting from readily available
m-xylene. A significant improvement of this procedure included application of the simple and commercially available reagents,
avoidance of expensive reagents and catalysts, simple operations and excellent yields.
# 2012 Qing Shan Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Deoxybenzoins; Isoflavanones; Synthesis
Isoflavanones as a group of natural products existing in plant are extensively studied for their immunosuppressive
[1], cytotoxic [2], anti-microbial [3], anti-HIV [4], estrogenic and anti-tumor activities [5]. The isoflavanone moiety is
the key structural feature of many synthetic intermediates to other phytoalexines such as pterocarpans and isoflavones.
Although some isoflavanone have been isolated from the leguminaceae family, the limited distribution in the plant
kingdom restricts further study on their bioactivities. This situation has prompted exploration toward chemical
synthesis of isoflavanones. There are several methods reported for the preparation of isoflavanones [6]. However, these
methods are unsatisfactory for many deficiencies such as expensive reagents and metallic catalysts, harsh reaction
conditions, complicated products, and toxic reagents. In this paper we presented a practical total synthetic route to
prepare a new series of isoflavanone.
Three classical methods for synthesizing isoflavanones were reported in literatures: (1) reduction of readily
available alkoxyisoflavones using a noble metal catalyst or complex metal hydrides [7]; (2) Heck arylation of 4-
acyloxy-2H-chromenes with aryl mercury (II) compounds in the presence of catalytic amounts of palladium acetate
[8]; (3) addition of a single carbon at the benzylic position of deoxybenzoins followed by cyclization [9]. Our strategy
reported here involved annulation of deoxybenzoins to form isoflavanones. And the protection for hydroxyl group and
cyclization are the most critical two synthetic steps in this route. Although various conditions were attempted in our
work, the protection for hydroxyl group of deoxybenzoins by chloromethyl ethyl ether (CMEE) or chloromethyl
methyl ether (CMME) was complicated and very low yields of the desired compounds were obtained. Fortunately
immediate success was achieved by using dimethyl sulfate. In order to cyclize deoxybenzoins [10], commercially
available CMEE was examined firstly, but the produced olefine ketone hardly converted to isoflavanones by treatment
with DBU (Scheme 1) [11]. To our delight, however, the further synthesis proceeded favorably in one step with
paraformaldehyde as the reactant (Scheme 2).
* Corresponding author.
E-mail address: qingshanl@yahoo.com (Q.S. Li).
1001-8417/$ – see front matter # 2012 Qing Shan Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.020

9[(Schme_1)TD$FIG] 08
J.N. Liu et al. / Chinese Chemical Letters 23 (2012) 907–910
Scheme 1. Preliminary attempts to cyclize deoxybenzoins with CMEE and DBU. (a) ClCH2OC2H5, K2CO3, acetone and (b) DBU, THF.
[(Schme_2)TD$FIG]
Scheme 2. Reagents and conditions: (a) H2SO4, HNO3, 110 8C, 3 h; (b) hydrochloric acid, Sn, 100 8C, 3–5 h, then, pH 3–4, 100 8C, 24 h; (c) HCl,
ZnCl2, nitrile, Et2O, 0 8C, 2.5 h, then, 4 8C, 12 h; (d) Me2SO4, K2CO3, Me2CO; (e) (CH2O)n, Et2NH, EtOH; (f) BBr3, CH2Cl2.
Deoxybenzoins 4 were key intermediates which were obtained conveniently by the Houben-Hoesch condensation
of 2 with different substituted benzacetonitril followed by partial methylation of the resulting 3. Then deoxybenzoins 4
were condensated with paraformaldehyde in the presence of diethylamine and anhydrous ethanol to afford the
corresponding methylated isoflavanones 5. Final removal of the methyl groups was accomplished with BBr3, which
afforded the hydroxylated isoflavanones 6 in high yields.
1. Experimental
1H NMR and 13C NMR spectra were recorded on a Bruker Avance-400 FT nuclear magnetic resonance
spectrometer with TMS as the internal standard. MS spectra were taken on a high resolution ESI-FTICR mass
spectrometer (Varian 7.0T). The melting points were determined on an XT4 melting point apparatus. All the reagents
were of analytical grade.
Compound 1: m-Xylene (2.4 mL, 19 mmol) was subjected to a mixture of sulfuric acid (6 mL) and nitric acid
(3 mL) below 40 8C. Then, nitrosonitric acid (3 mL) was added to the above solution. The mixture was heated at
110 8C for 3 h, and then followed by filtration to yield compound 1 as a white solid 4.3 g (96.0%) [12].
Compound 2: A mixture of compound 1 (9.0 g, 37 mmol) and Sn powder (36 g, 200 mmol) was added to
hydrochloric acid (95 mL). The mixed solution was stirred at 60 8C until the solid was completely dissolved. And then
the solution was heated at 100 8C for 3–5 h. On cooling, the mixture was adjusted to pH 3–4. Then, the solution was
refluxed for 24 h. The solution was extracted with diethyl ether, and the organic phase was dried with anhydrous
sodium sulfate, evaporated at a reduced pressure to form compound 2 as a yellow solid 3.7 g (64.6%) [13].
Compound 3: Dry hydrogen chloride was bubbled through the cold solution of compound 2 (3.1 g, 20 mmol) and
the corresponding cyanide (20 mmol) in the anhydrous ether containing dry zinc chloride (1.4 g, 10 mmol) with
vigorous stirring for 2.5 h. The ketimine hydrochloride could separate out as a yellow solid for fully placed at 4 8C.
After decanting off the solvent, the solid was dissolved in water and refluxed for 1 h, and the yellow solid emerged was
collected to give compound 3.
Compound 4: To a solution of 3 (3 mmol) in dry acetone were added anhydrous potassium carbonate (6 mmol) and
dimethyl sulfate (6 mmol), the mixture was refluxed at 70 8C for 45 min with TLC monitoring. After the reaction was
complete the reaction mixture was filtered hot, washed with acetone and the filtrate was concentrated to prepare
compound 4.

J.N. Liu et al. / Chinese Chemical Letters 23 (2012) 907–910
909
Compound 5: Compound 4 (1 mmol) was dissolved in ethanol and refluxed with paraformaldehyde (2 mmol) and
diethylamine (2 mmol) for 1–1.5 h. The progress of the reaction was monitored by TLC. Ethanol was removed and the
mixture was acidified with diluted acid. The desired isoflavanone 5 was purified by chromatography column.
Compound 6: The removal of the methyl groups of compound 5 (1 mmol) was accomplished by using boron
tribromide (5 mL, 1 mol/L) in DCM to generate isoflavanone 6.
1
5a: Oil (78.2% yield); H NMR (400 MHz, CDCl3): d 7.34 (m, 5H), 4.68 (d, 2H, J = 7.01 Hz), 3.92 (t, 1H,
J = 7.12 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d 190.54, 163.31,
159.66, 158.03, 135.57, 128.79, 128.56, 127.60, 118.81, 115.35, 111.937, 70.82, 61.07, 60.13, 52.94, 8.89, 8.65; ESI-
MS (m/z): 310.9 ([MÀH]À); HR-MS 335.1257 ([M+Na]+; Calcd. for C19H20NaO4 335.1254).
5b: White solid (74.3% yield), mp 66.0–66.9 8C; 1H NMR (400 MHz, CDCl3): d 7.27(d, 2H, J = 8.57 Hz), 7.06 (d,
2H, J = 8.70 Hz), 4.67 (dd, 1H, J = 5.38, 11.38 Hz), 4.62 (dd, 1H, J = 8.50, 11.42 Hz), 3.90 (dd, 1H, J = 5.40,
8.43 Hz), 3.79 (s, 3H), 3.78 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d 190.33, 163.44, 161.02,
159.56, 158.04, 131.27, 130.18, 130.11, 118.97, 115.82, 115.60, 115.42, 111.76, 70.73, 61.06, 60.15, 52.12, 8.89,
8.65; ESI-MS (m/z): 329.1([MÀH]À); HR-MS 353.1162 ([M+Na]+; Calcd. for C19H19FNaO4 353.1160).
5c: White solid (77.6% yield), mp 84.6–86.7 8C; 1H NMR (400 MHz, CDCl3): d 7.34 (d, 2H, J = 8.54 Hz), 7.24 (d,
2H, J = 8.41 Hz), 4.67 (dd, 1H, J = 5.46, 11.40 Hz), 4.63 (dd, 1H, J = 8.20, 11.42 Hz), 3.89 (dd, 1H, J = 5.50,
8.23 Hz), 3.79 (s, 3H), 3.77 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d 190.01, 163.50, 159.53,
158.05, 133.97, 133.56, 129.89, 128.96, 119.01, 115.43, 111.72, 70.51, 61.07, 60.15, 52.21, 8.884, 8.65; ESI-MS (m/
z): 347.1 ([M+H]+); HR-MS 369.0866 ([M+Na]+; Calcd. for C19H19ClNaO4 369.0864).
5d: White solid (75.5% yield), mp 63.6–65.3 8C; 1H NMR (400 MHz, CDCl3): d 7.22 (d, 2H, J = 8.65 Hz), 6.90
(d, 2H, J = 8.75 Hz), 4.66 (dd, 1H, J = 5.73, 11.39 Hz), 4.63 (dd, 1H, J = 8.29, 11.37 Hz), 3.87 (dd, 1H, J = 5.72,
8.24 Hz), 3.91 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d
190.87, 163.24, 159.63, 159.00, 158.00, 129.58, 127.50, 118.75, 115.32, 114.25, 111.89, 70.89, 61.06, 60.13,
55.27, 52.11, 8.90, 8.64; ESI-MS (m/z): 343.2 ([M+H]+); HR-MS 365.1357 ([M+Na]+; Calcd. for C20H22NaO5
365.1359).
5e: White solid (73.6% yield), mp 102.4–103.4 8C; 1H NMR (400 MHz, CDCl3): d 7.48 (d, 1H, J = 2.13 Hz), 7.26
(dd, 1H, J = 2.14, 8.51 Hz), 7.11 (d, 1H, J = 8.35 Hz), 4.53 (m, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.19 (s, 3H), 2.16 (s,
3H); 13C NMR (100 MHz, CDCl3): d 189.32, 163.60, 159.81, 158.09, 135.40, 134.14, 132.12, 131.04, 129.78, 127.49,
119.14, 115.55, 112.26, 69.84, 61.07, 60.17, 50.24, 8.87, 8.69; ESI-MS (m/z): 381.2 ([M+H]+); HR-MS 403.0476
([M+Na]+; Calcd. for C19H18Cl2NaO4 403.0473).
5f: Viscous oil (69.4% yield); 1H NMR (400 MHz, CDCl3): d 7.18 (s, 4H), 4.65 (m, 2H), 3.89 (m, 1H), 3.80 (s, 3H),
3.76 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d 190.77, 163.24, 159.67, 158.01,
137.27, 132.43, 129.50, 128.40, 118.74, 115.31, 111.94, 70.85, 61.07, 60.12, 52.57, 21.11, 8.89, 8.64; ESI-MS (m/z):
327.6 ([M+H]+); HR-MS 349.1415 ([M+Na]+; Calcd. for C20H22NaO4 349.1411).
6a: Yellow solid (90.1% yield), mp 136.6–138.4 8C; 1H NMR (400 MHz, DMSO-d6): d 12.39 (s, 1H), 7.35 (m, 5H),
4.65 (dd, 1H, J = 5.24, 11.34 Hz), 4.59 (dd, 1H, J = 8.33, 11.29 Hz), 3.97 (dd, 1H, J = 5.22, 8.23 Hz), 2.09 (s, 3H),
2.09 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 196.87, 160.98, 159.75, 157.77, 135.26, 128.94, 127.90, 103.11,
102.82, 101.83, 71.23, 51.29, 7.47, 6.94; ESI-MS (m/z): 285.5 ([M+H]+); HR-MS 283.0974 ([MÀH]À; Calcd. for
C17H15O4 283.0976).
6b: Yellow solid (93.4% yield), mp 184.0–186.0 8C; 1H NMR (400 MHz, DMSO-d6): d 12.37 (s, 1H), 9.82 (s, 1H),
7.34 (m, 2H), 7.18 (m, 2H), 4.60 (d, 2H, J = 6.96 Hz), 4.21 (t, 1H, J = 6.89 Hz), 1.98 (s, 3H), 1.97 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d 197.35, 163.05, 160.46, 159.26, 157.84, 131.50, 131.30, 131.22, 115.91, 115.69, 103.91,
102.83, 102.17, 71.01, 49.80, 8.61, 8.11; ESI-MS (m/z): 300.9 ([MÀH]À); HR-MS 301.0880 ([MÀH]À; Calcd. for
C17H14FO4 301.0882).
6c: Yellow solid (95.5% yield), mp 157.5–158.6 8C; 1H NMR (400 MHz, DMSO-d6): d 12.34 (s, 1H), 9.77 (s, 1H),
7.42 (d, 2H, J = 8.47 Hz), 7.32 (d, 2H, J = 8.47 Hz), 4.60 (d, 2H, J = 6.89 Hz), 4.22 (t, 1H, J = 6.88 Hz), 1.98 (s, 3H),
1.97 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 197.07, 163.11, 159.27, 157.82, 135.23, 132.64, 131.17, 128.98,
103.95, 102.87, 102.18, 70.86, 49.91, 8.61, 8.11; ESI-MS (m/z): 316.8 ([MÀH]À); HR-MS 317.0584 ([MÀH]À;
Calcd. for C17H14ClO4 317.0586).
6d: Yellow solid (94.1% yield), mp above 300 8C; 1H NMR (400 MHz, DMSO-d6): d 12.46 (s, 1H), 9.73 (s, 1H),
7.07 (d, 2H, J = 8.57 Hz), 6.73 (d, 2H, J = 8.59 Hz), 4.54 (d, 2H, J = 7.52 Hz), 3.99 (t, 1H, J = 7.28 Hz), 1.97 (s, 3H),
1.96 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 198.02, 162.90, 159.28, 157.86, 157.14, 130.13, 126.41, 115.79,

910
J.N. Liu et al. / Chinese Chemical Letters 23 (2012) 907–910
103.80, 102.72, 102.18, 71.32, 49.78, 8.63, 8.12; ESI-MS (m/z): 301.4 ([M+H]+); HR-MS 299.0922 ([MÀH]À; Calcd.
for C17H15O5 300.0998).
6e: Yellow solid (94.4% yield), mp 204.6–206.2 8C; 1H NMR (400 MHz, DMSO-d6): d 12.24 (s, 1H), 9.81 (s, 1H),
7.70 (d, 1H, J = 2.16 Hz), 7.45 (dd, 1H, J = 2.17, 8.41 Hz), 7.37 (d, 1H, J = 8.41 Hz), 4.62 (m, 3H), 1.99 (s, 3H), 1.98
(s, 3H); 13C NMR (100 MHz, DMSO-d6): d 195.87, 163.19, 159.23, 157.81, 135.27, 133.63, 132.71, 132.67, 129.58,
128.12, 104.14, 103.11, 102.37, 69.58, 43.36, 8.61, 8.12; ESI-MS (m/z): 350.8 ([MÀH]À); HR-MS
351.0197([MÀH]À; Calcd. for C17H13Cl2O4 351.0196).
6f: Yellow solid (89.7% yield), mp 149.3–151.2 8C; 1H NMR (400 MHz, DMSO-d6): d 12.43 (s, 1H), 9.74 (s, 1H),
7.16 (s, 4H), 4.58 (d, 2H, J = 6.62 Hz), 4.09 (t, 1H, J = 6.63 Hz), 2.28 (s, 3H), 1.96 (s, 6H); 13C NMR (100 MHz,
DMSO-d6): d 197.69, 162.98, 159.29, 157.87, 137.03, 133.30, 129.57, 129.02, 103.84, 102.77, 102.25, 71.19, 50.19,
21.12, 8.62, 8.11; ESI-MS (m/z): 299.4 ([M+H]+); HR-MS 297.1134 ([MÀH]À; Calcd. for C18H17O4 297.1132).
In conclusion, we developed a convenient six-step synthetic approach for isoflavanones from m-xylene, and 12 new
desired products were obtained. Comparing with the classical methods [7–9], this practical synthetic strategy could
produce various methylated and hydroxylated isoflavanones by using commercially available cheap reagents with
simple operations and excellent yields. The pharmacological study of the new isoflavanones is ongoing.
Acknowledgment
We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No.
81172938) and the Top science and Technology Innovation Teams of Teams of Higher Learning Institutions of Shanxi.
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