Synthesis of unsymmetrical benzil licoagrodione

Article abstract of DOI:10.1021/jo8013353

(Chemical Equation Presented) A synthesis of unsymmetrical 1,2-diarylethane-1,2-dione is reported involving the intramolecular cyclization of anionic benzylic ester of the aryl benzyl ether followed by oxidation employing dioxirane. With the use of microwave irradiation, licoagrodione was prepared from Claisen rearrangement of the corresponding allyl phenyl ether 1,2-diketone readily available from the Lindlar's reduction of the corresponding alkyne derivative. Subsequent removal of protecting groups then furnished the desired product.

Full text of DOI:10.1021/jo8013353

Synthesis of Unsymmetrical Benzil Licoagrodione
Rattana Worayuthakarn,† Sasiwadee Boonya-udtayan,‡
Eakarat Arom-oon,† Poonsakdi Ploypradith,†,‡
Somsak Ruchirawat,†,‡,§ and Nopporn Thasana*,†,‡
Laboratory of Medicinal Chemistry, Chulabhorn Research
Institute, Laksi, Bangkok 10210, Thailand, Program on
Chemical Biology, Chulabhorn Graduate Institute, Laksi,
Bangkok 10210, Thailand, and Program on Research and
DeVelopment of Synthetic Drugs, Institute of Science and
Technology for Research and DeVelopment, Mahidol
UniVersity, Salaya Campus, Nakhon Pathom 73170, Thailand
FIGURE 1. Unsymmetrical and symmetrical natural benzils.
nopporn@cri.or.th
flavanoids as common constituents of plants in the Leguminosae
family, and have been used as intermediates for the synthesis
of various flavonoids (Figure 1).4 Licoagrodione (1), isolated
from a Chinese herb, Glycyrrhiza glabra (licorice), was found
to exhibit antimicrobial activity,5 while its backbone, 2,2′,4-
trihydroxy-4′-methoxybenzil (2), has been isolated from the
wood of Zollernia paraensis.6 Scandione (3) was isolated from
the stem of a Thai medicinal plant, Derris scandens, and showed
antibacterial, hypertensive, and radical scavenging activities.7
Lespedezol H1 (4) was isolated from the stem of Lespedeza
homoloba,8 and its benzil C-glycoside, vijayosin (5), was
isolated from Pterocarpus marsupium, which has been used as
an ayurvedic drug in India.9 Not only isolated from various
plants, the heteroaryl-1,2-diketones, 1,2-bis(1H-indol-3-yl)e-
thane-1,2-dione (6) and hyrtiosin B (7), were also isolated from
marine sponges, Smennospongia sp.10 and Hyrtios erectus,11
respectively.
We recently described the synthesis of 2-phenylbenzofuran-
3-carboxylic acid involving the rearrangement of aromatic
cyanohydrin carbonate esters and intramolecular cyclization of
the benzylic carbanion using LDA.12 With the initial intention
to synthesize wrightiadione (11),13 lithiation of active methylene
protons of ketone 9 followed by reaction with methyl-O-
benzylsalicylate 8a was thought to smoothly afford 1,3-diketone
10 (Scheme 1). Unfortunately, no target compound 10 was
observed, but unexpected product was obtained in moderate
yield. The product was charecterized as 2-hydroxy-1,2-diphe-
ReceiVed June 27, 2008
A synthesis of unsymmetrical 1,2-diarylethane-1,2-dione is
reported involving the intramolecular cyclization of anionic
benzylic ester of the aryl benzyl ether followed by oxidation
employing dioxirane. With the use of microwave irradiation,
licoagrodione was prepared from Claisen rearrangement of
the corresponding allyl phenyl ether 1,2-diketone readily
available from the Lindlar’s reduction of the corresponding
alkyne derivative. Subsequent removal of protecting groups
then furnished the desired product.
Benzils, 1,2-diarylethane-1,2-diones, are an important class
of compounds for organic synthesis as the synthetic studies of
both symmetrical and unsymmetrical benzils have been
reported.1,2 Some benzils exhibited various potential biological
activities including inhibition of mammalian carboxylesterases
(CE).3 They were often isolated concurrently with other
† Chulabhorn Research Institute.
‡ Chulabhorn Graduate Institute.
(4) (a) Brady, W. T.; Gu, Y.-Q. J. Org. Chem. 1988, 53, 1353–1356. (b)
Schwarz, J. S. P.; Cohen, A. I.; Ollis, W. D.; Kaczka, E. A.; Jackman, L. M.
Tetrahedron 1964, 20, 1317–1330.
(5) Li, W.; Asada, Y.; Yoshikawa, T. Planta Med. 1998, 64, 746–747.
(6) Ferrari, F.; Alves de Lima, R.; Marini Bettolo, G. B. Phytochemistry
1984, 23, 2691–2692.
(7) Mahabusarakam, W.; Deachathai, S.; Phongpaichit, S.; Jansakul, C.;
Taylor, W. C. Phytochemistry 2004, 65, 1185–1189.
(8) Miyase, T.; Sano, M.; Yoshino, K.; Nonaka, K. Phytochemistry 1999,
52, 311–319.
(9) Maurya, R.; Singh, R.; Deepak, M.; Handa, S. S.; Yadav, P. P.; Mishra,
P. K. Phytochemistry 2004, 65, 915–920.
(10) McKay, M. J.; Carroll, A. R.; Quinn, R. J.; Hooper, J. N. A. J. Nat.
Prod. 2002, 65, 595–597.
(11) Salmoun, M.; Devijver, C.; Daloze, D.; Braekman, J.-C.; van Soest,
R. W. M. J. Nat. Prod. 2002, 65, 1173–1176.
(12) Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.; Ruchirawat, S.
Tetrahedron Lett. 2003, 44, 1019–1021.
§ Mahidol University.
(1) For the synthesis of symmetrical benzil, see: (a) Schraufstatter, E. Chem.
Ber. 1948, 235–239. (b) Schraufstatter, E. Chem. Ber. 1948, 240–242. (c)
VanAllan, J. A. J. Org. Chem. 1958, 23, 1679–1682. (d) Mohr, B.; Enkelmann,
V.; Wegner, G. J. Org. Chem. 1994, 59, 635–638. (e) Nudelman, N.; Schulz, H.
J. Chem. Res. (S) 1999, 422–423. (f) Kwon, T. W.; Song, S. J.; Kwon, Y. U.;
Chung, S, K. Bull. Korean Chem. Soc. 2003, 24, 229–231. (g) Yasuike, S.; Kishi,
Y.; Kawara, S.-i.; Kurita, J. Chem. Pharm. Bull. 2005, 53, 425–427.
(2) For the synthesis of unsymmetrical benzil, see: (a) Suginome, H. J. Org.
Chem. 1958, 23, 1044–1046. (b) Walsh, C. J.; Mandal, B. K. J. Org. Chem.
1999, 64, 6102–6105. (c) Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; de Laszlo,
S.; Koch, G.; Li, B.; MacCoss, M.; Mantlo, N.; O’Keefe, S.; Pang, M.; Rolando,
A.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 2001, 11, 2549–2553. (d)
Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.; Tretyakov, E. V.; Knight,
D. W. Tetrahedron 2002, 58, 1607–1610. (e) Katritzky, A. R.; Zhang, D.;
Kirichenko, K. J. Org. Chem. 2005, 70, 3271–3274.
(3) Wadkins, R. M.; Hyatt, J. L.; Wei, X.; Yoon, K. J. P.; Wierdl, M.;
Edwards, C. C.; Morton, C. L.; Obenauer, J. C.; Damodaran, K.; Beroza, P.;
Danks, M. K.; Potter, P. M. J. Med. Chem. 2005, 48, 2906–2915.
(13) (a) Ruchirawat, S.; Thasana, N. Synth. Commun. 2001, 31, 1765–1769.
(b) Thasana, N.; Ruchirawat, S. Synlett 2003, 1037–1039.
7432 J. Org. Chem. 2008, 73, 7432–7435
10.1021/jo8013353 CCC: $40.75 2008 American Chemical Society
Published on Web 08/20/2008

SCHEME 1. Initial Research Goal
SCHEME 2. Proposed Mechanism for the Formation of 12
TABLE 2. Preparation of 2-Hydroxy-2′-methoxy-4′-methoxybenzil
18
TABLE 1. Optimization of the Anionic Benzylic Ester
Rearrangement
entry
condition
yield of 18 (%)
1
2
3
4
5
4.0 equiv of LTMP, THF, -78 °C, then O2
4.0 equiv of LTMP, THF, -78 °C, dioxirane
4.0 equiv of LTMP, THF, -78 °C, then O2
4.0 equiv of LTMP, THF, -40 °C, dioxirane
4.5 equiv of LTMP, THF, -40 °C, dioxirane
a, 47
a, 50
b, 16
b, 48a
b, 54
yield (%)
Aa Bb
entry
12
R1
R2
R3
1
2
3
4
5
6
a
b
c
d
e
f
H
H
OMe
OMe
H
H
H
H
H
NO2
H
H
OMe
H
OMe
H
NO2
43c
31
16
16
58
53
33
a 15% recovery of benzyl ester 17b.
39
NAd
NAe
LDA while using dimethyldioxirane (DMDO) as the source of
oxygen atom (condition B),16 the yield was dramatically
improved (Table 1, condition B, entries 1 to 4). The presence
of an electron-withdrawing nitro group at the ortho or para
position of the aromatic benzyl ether gave the complex mixture
and recovered starting material in 27% and 13% yield (Table
1, entries 5 and 6), respectively, as previously reported by
Scaiano.17 LHMDS was also studied in this condition and gave
no reaction.
The proposed mechanism was shown in Scheme 2. The
benzylic carbanion of benzyl ether 8 could intramolecularly
cyclize to give 2-phenylbenzofuranone 13, which could be
converted to the corresponding anion 14 and reacted spontane-
ously with dioxirane leading to the hemiketal anion 15.
Subsequent loss of acetone gave 2-hydroxy-2-phenylbenzofuran-
3-one 16, which, upon ring opening, furnished 2-hydroxybenzil
12.
Having successfully synthesized unsymmetrical benzils,
we then applied the above approach (condition B) to the
synthesis of licoagrodione (1). 2-Hydroxy-4-isopropoxy-2′-
methoxymethoxy-4′-methoxybenzil 18a was used as the licoa-
grodione backbone and was synthesized from methyl 4-isopro-
poxy-2-(4-methoxy-2-(methoxymethoxy)benzyloxy)benzoate
17a. With the optimized condition, increasing the amount of
base to 4 equiv of LTMP gave benzil 18a in 47-50% yield
(Table 2, entries 1 and 2).
H
a Condition A: 2 equiv of LDA, THF, -78 °C. b Condition B: 3
equiv of LTMP, THF, -78 °C, then dioxirane. c 46% of benzil 12a was
obtained after addition of oxygen gas. d 4 equiv of LTMP was used and
gave 27% recovery of benzyl ester 8e. e 13% recovery of benzyl ester
8f.
nylethane-1,2-dione 12a on the basis of spectroscopic and
analytical data with a singlet of hydroxy proton at δ 11.39 in
the H NMR spectrum and the dicarbonyl groups at 1677 and
1
1643 cm-1 in the IR spectrum.
This unexpected result prompted us to investigate the potential
application of this finding for the construction of natural
unsymmetrical benzils using the intramolecular cyclization of
anionic benzylic ester of the aryl benzyl ether and subsequent
oxygenation. General methods for deprotonating the benzylic
ether proton involve the photochemical hydrogen atom abstrac-
tion reaction14 or the hindered nonionic phosphazene base.15
Herein we developed a concise method for the synthesis of
unsymmetrical benzils by the deprotonation of the benzylic ether
using lithiated bases (LDA and LTMP) in anhydrous media
followed by reacting the intermediate with molecular oxygen
or with dioxirane to afford benzil 12. Methyl-O-benzylsalicylate
derivatives 8a-f were used as prototypes in this study. Our
results are summarized in Table 1.
Treating simple benzylic ether 8a with 2 equiv of LDA
(condition A) gave 2-hydroxybenzil 12a in moderate yields
either in the presence or the absence of the molecular oxygen
gas (Table 1, condition A, entry 1). The electron-donating groups
on both aromatic rings gave lower yields of the corresponding
products under the same condition (Table 1, entries 2 to 4).
When 3 equiv of LTMP was employed instead of 2 equiv of
The structure of benzil 18a was fully supported by spectro-
scopic data at δ 190.0 and 197.6 in the 13C NMR for the two
carbonyl peaks. The “C-5” Dimethylallyl group equivalent was
introduced into the molecule as the corresponding alkynyl ether
of the phenolic group by reacting 18a with 3-chloro-3-
methylbut-1-yne and NaH in DMF in 92% yield.18 The alkyne
(16) (a) Pabuccuoglu, V.; Hesse, M. Heterocycles 1997, 45, 1751. (b) Barbier,
D.; Marazano, C.; Das, B. C.; Potier, P. J. Org. Chem. 1996, 61, 9596.
(17) Font-Sanchis, E.; Aliaga, C.; Cornejo, R.; Scaiano, J. C. Org. Lett. 2003,
5, 1515–1518.
(14) Kraus, G. A.; Zhang, N. J. Org. Chem. 2000, 65, 5644–5646.
(15) Kraus, G. A.; Zhang, N.; Verkade, J. G.; Nagarajan, M.; Kisanga, P.
Org. Lett. 2000, 2, 2409–2410.
J. Org. Chem. Vol. 73, No. 18, 2008 7433

SCHEME 3. Preparation of Allyl Aryl Ether 1,2-Diketones
20
SCHEME 5. Synthesis of Licoagrodione (1)
SCHEME 4. The Claisen Rearrangement and Deprotection
Reactions
the required benzil then started from methyl benzoate 17b.
Under reaction condition similar to those for the synthesis of
compound 18a, the benzil 18b was obtained in 16-48% yield
(Table 2, entries 3 to 4). With the use of MOM as the protecting
group in place of the isopropyl group, increasing the amount
of base to 4.5 equiv of LTMP while raising the temperature to
-40 °C gave the desired product 18b in better yield (Table 2,
entry 5). The O-alkylation of benzil 18b with 3-chloro-3-
methylbut-1-yne following Lindlar’s reduction gave 20b in good
overall yield (Scheme 3).
The microwave irradiation at 150 °C for 5 min assisted the
Claisen rearrangement of 20b to yield an inseparable mixture
of 21c and 21d. Increasing the reaction time to 30 min furnished
the ultimate target licoagrodione (1) in 14% yield with the
cyclization congener 23 and 24 in 10% and 11% yield,
respectively (Scheme 5). Subsequent hydrolysis of the MOM
ether of the product from the Claisen rearrangement 21c and
21d with 23 equiv of HCl in MeOH at 40-45 °C for 90 min
afforded the licoagrodione (1) in moderate yield (42%).24
In summary, we have developed a facile route for the
unsymmetrical benzils 12 and 18. Compounds 18a and 18b lend
themselves to conversions to various natural benzils, and were
also applied to the synthesis of licoagrodione (1). The key
reactions are (1) the intramolecular cyclization of the anionic
benzylic ester of methyl O-benzyl salicylate derivatives followed
by the oxygenation with dioxirane, (2) the Claisen rearrangement
under neutral condition using microwave irradiation, and (3)
hydrolysis of the MOM ether under relatively mild conditions.
This methodology should be valuable for the synthesis of
unsymmetrical benzils and we are applying this methodology
to the synthesis of related benzils and other biologically
important oxygen heterocyclic compounds.
19a was characterized and the alkyne absorption was observed
at 3263 cm-1. Hydrogenaton of alkyne 19a under 10% Pd-
BaSO4 in CH2Cl2 yielded the 2-methylbut-3-en-2-yloxy ether
20a in 87% yield (Scheme 3).19
The Claisen rearrangement of 20a under refluxing N,N-
diethylaniline followed by the deprotection of both MOM and
isopropyl ethers with 6 N HCl afforded the isopropyl ether
licoagrodione 21a in 52% yield. However licoagrodione (1) was
not obtained by using this acidic deprotection reaction.
Moody20 reported the Claisen rearrangement of the allyl group
under refluxing of DMF. We then modified the rearrangement
of 20a using microwave irradiation. Under the microwave
irradiation at 150 °C for 20 min, the isopropyl ether 21a and
its congener the MOM ether 21b were obtained in 32% and
24% yields, respectively (Scheme 4). All attempts to cleave the
isopropyl ether of 21a with use of AlCl3 in CH2Cl2,21 Si-tosic
acid in toluene at 65 °C,22 and acetic acid at 55 °C23 with a
catalytic amount of sulfuric acid led only to the cyclization
product, dihydrobenzopyranethane-1,2-dione 22, in moderate to
good yields while none of the target licoagrodione (1) was
obtained.
Experimental Section
We then turned to the use 2-hydroxy-2′,4-di(methoxymethoxy)-
4′-methoxybenzil 18b as the benzil skeleton and synthesis of
1-(2-Hydroxy-4-isopropoxyphenyl)-2-(4-methoxy-2-O-meth-
oxymethylphenyl)ethane-1,2-dione (18b). A solution of LTMP
(2.25 mmol, 4.5 equiv) was prepared by dropwise addition of
n-BuLi (2.62 M in hexane) (0.86 mL, 2.25 mmol) into tetrameth-
ylpiperidine (0.79 mL, 4.5 mmol) in dry THF (5 mL) under argon
atmosphere at -78 °C. The mixture was then warmed to 0 °C and
stirred at this temperature for 1 h. The ice-water bath was replaced
with a dry ice/CH3CN bath, and a solution of methyl 2-(4-methoxy-
2-O-methoxymethylbenzyloxy)-4-O-alkoxylbenzoate 17b (196 mg,
0.5 mmol, 1 equiv) in dry THF (1 mL) was added and the solution
was stirred at this temperature for 1 h. The pale yellow solution
(18) Pernin, R.; Muyard, F.; Be´valot, F.; Tillequin, F.; Vaquette, J. J. Nat.
Prod. 2000, 63, 245–247.
(19) (a) Gruttadauria, M.; Noto, R.; Deganello, G.; Liotta, L. F. Tetrahedron
Lett. 1999, 40, 2857–2858. (b) Henrick, C. A. Tetrahedron 1977, 33, 1845–
1889.
(20) (a) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem.
2005, 70, 4414–4422. (b) Burlison, J. A.; Neckers, L.; Smith, A. B.; Maxwell,
A.; Blagg, B. S. J. J. Am. Chem. Soc. 2006, 128, 15529–15536.
(21) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem. 1998, 63,
9139–9144.
(22) Ploypradith, P.; Cheryklin, P.; Niyomtham, N.; Bertoni, D. R.; Ruchira-
wat, S. Org. Lett. 2007, 9, 2637–2640.
(23) Tietze, L. F.; Singidi, R. R.; Gericke, K. M. Org. Lett. 2006, 8, 5873–
5876.
(24) Hastings, J. M.; Hadden, M. K.; Blagg, B. S. J. J. Org. Chem. 2008,
73, 369–373.
7434 J. Org. Chem. Vol. 73, No. 18, 2008

turned orange and dimethyldioxirane (5 mL) was added dropwise
at -40 °C. The resulting mixture was quenched with saturated
NH4Cl and extracted with EtOAc (3 × 25 mL), washed with water
and brine, dried over anhydrous Na2SO4, and concentrated to give
yellow oil, which was purified by PLC using 20% EtOAc in hexane
as developing solvent to afford 2′-hydroxy-1,2-diarylethanediones
18b (102.2 mg, 54%) as a pale yellow oil: IR (UATR) νmax 2959,
2927, 1620, 1595, 1573, 1501, 1245, 1217, 1152, 1120, 1077, 984,
922, 865, 781, 735 cm-1; 1H NMR (400 MHz, CDCl3) δ 11.66 (s,
1H), 8.05 (d, J ) 8.9 Hz, 1H), 7.35 (d, J ) 8.8 Hz, 1H), 6.71 (dd,
J ) 8.9, 2.2 Hz, 1H), 6.67 (d, J ) 2.3 Hz, 1H), 6.61 (d, J ) 2.2
Hz, 1H), 6.51 (dd, J ) 8.8, 2.3 Hz, 1H), 5.21 (s, 2H), 4.95 (s, 2H),
3.87 (s, 3H), 3.47 (s, 3H), 3.18 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.6, 190.0, 166.8, 165.3, 163.9, 159.9, 133.4, 132.6,
116.8, 111.4, 108.7, 108.5, 103.8, 99.9, 94.1, 94.0, 56.4 (2C), 55.8;
EI-MS m/z (%) 375 (M+ - 1, 1), 195 (100), 181 (13), 167 (8),
165 (52), 151 (23); HRMS (microTOF) calcd for C19H20O8Na
399.1050, found 399.1054.
Licoagrodione (1). In a 10 mL microwave vessel, 1-[2-(1,1-
dimethylallyloxy)-4-O-methoxymethylphenyl]-2-(4-methoxy-2-O-
methoxymethylphenyl)ethane-1,2-dione 20b (48.5 mg, 0.109 mmol)
was dissolved in DMF (1 mL). The solution was heated in a
microwave reactor (200 W) at 150 °C for 5 min. The solution was
then diluted in ethyl acetate (15 mL) and washed with water (3 ×
10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered,
and evaporated to give red-brown oil as a mixture of 21c and 21d.
The mixture was then treated with a solution of (23 equiv) HCl in
MeOH (2.3 mL) and heated at 40-45 °C for 90 min. The reaction
was quenched by the addition of a saturated aqueous NaHCO3 and
extracted with ethyl acetate (3 × 10 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated to give red-brown oil. The crude product was then
purified by PLC using 30% EtOAc in hexane as developing solvent
to give yellow oil which was recrystallized with CH2Cl2 and hexane
to furnish licoagrodione (1) (16.3 mg, 42%) as a yellow solid: mp
126-127 °C (CH2Cl2-hexane); IR (UATR) νmax 3357, 1633, 1609
cm-1; 1H NMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 11.84 (s, 1H),
7.39 (d, J ) 9.0, 1H), 7.27 (d, J ) 8.4 Hz, 1H), 6.50 (d, J ) 9.0,
1H), 6.44 (dd, J ) 9.0, 2.4 Hz, 1H), 6.37 (d, J ) 8.4 Hz, 1H),
5.31-5.25 (m, 1H), 3.87 (s, 3H), 3.47 (d, J ) 7.2 Hz, 1H), 1.84
(s, 3H), 1.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.7 (2C),
167.7, 166.7, 163.8, 163.3, 136.2, 134.1, 132.2, 120.5, 114.5, 111.0,
110.8, 109.2, 108.9, 101.1, 55.8, 25.8, 21.5, 17.9; EI-MS m/z (%)
356 (M+, 8), 205 (100), 151 (28), 149 (31); HRMS (microTOF)
calcd for C20H21O6 (M + H)+ 357.1333, found 357.1334.
Acknowledgment. Financial support from the Thailand
Research Fund (TRF; RMU4980048 for N.T.) and The Center
for Toxicology, Environmental Health and Management of
Toxic Chemicals (CTEM) is gratefully acknowledged.
Supporting Information Available: General methods, ex-
perimental procedures, as well as spectroscopic data and copies
of NMR spectra of compounds (12a-d, 18a,b, 19a,b, 20a,b,
21a, 22, and 1). This material is available free of charge via
the Internet at http://pubs.acs.org.
JO8013353
J. Org. Chem. Vol. 73, No. 18, 2008 7435