The synthesis of wrightiadione via directed remote metalation

Article abstract of DOI:10.1055/s-2003-39313

The application of directed remote metalation (DreM) and electrophilic substitution is reported for the synthesis of wrightiadione using N,N-diethylcarboxamide as a directed metalation group (DMG) and electrophilic group. The lithiation of N,N-diethylisoflavone-2′-carboxamide with LDA gave a carbanion at C-2 which further cyclized to wrightiadione.

Full text of DOI:10.1055/s-2003-39313

LETTER
1037
The Synthesis of Wrightiadione via Directed Remote Metalation
Synthesis of
W
righ
o
tiadione pporn Thasana,a,b Somsak Ruchirawat*a,b,c
a
Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
Fax +66(2)5740616; E-mail: somsak@tubtim.cri.or.th.
b
c
Department of Chemistry, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Programme on Research and Development of Synthetic Drugs, Institute of Science and Technology for Research and Development,
Mahidol University, Salaya Campus, Thailand
Received 27 February 2003
Chromones unsubstituted at C-2 are susceptible to ring
cleavage and consequently C-2 lithiation is difficult to
achieve. Although the evidence is not strong, it does sup-
port a preference for 3- over 2-lithiation. Lithiation at both
Abstract: The application of directed remote metalation (DreM)
and electrophilic substitution is reported for the synthesis of wright-
iadione using N,N-diethylcarboxamide as a directed metalation
group (DMG) and electrophilic group. The lithiation of N,N-dieth-
ylisoflavone-2¢-carboxamide with LDA gave a carbanion at C-2 positions can be improved by appropriate substituents.
which further cyclized to wrightiadione.
With an acetal at position 3, chromone derivatives were
readily lithiated at position 2 and the anion could be cap-
Key words: directed remote metalation, wrightiadione, N,N-dieth-
ylisoflavone-2¢-carboxamide, directed metalation group, electro-
philic substitution
tured with electrophiles.7
On the basis of this pioneering work, we have developed
a strategy for the synthesis of wrightiadione 1. We envis-
aged that the carbanion at C-2 of N,N-diethylisoflavone-
2¢-carboxamide 4 could be generated under remote meta-
lation conditions using N,N-diethylcarboxamide as a di-
rected metalation group (DMG). The resulting carbanion
3 could counter attack with the N,N-diethylcarboxamide
functioning as an electrophile to give the product 1. The
key intermediate isoflavone 4 could be prepared from 2-
hydroxybenzoin 5 using a C1 addition procedure as shown
in a general method for the synthesis of isoflavones.8
Compound 5 could be prepared from the lateral lithiation
reaction9 of toluamide 7 with methyl salicylate 6 as shown
in Scheme 1.
Wrightiadione 1 is a rare and unusual oxygen heterocycle
isolated from the bark of Wrightia tomentosa, a medicinal
plant of Thailand, and it has been shown to exhibit cyto-
toxicity against a cultured murine P388 lymphocytic leu-
kemia cell line (ED50 1.1 mgmL–1). The methanol extract
of the dried leaves and stems of this plant also exhibited
weak activity against HIV-1 reverse transcriptase.1 Re-
cently we have disclosed a successful synthesis of
wrightiadione2 1 and also isowrightiadione3 2, an isomeric
compound.
O
O
O
O
O
O
Li+
NEt2
O
O
NEt2
_
1
O
O
1
O
2
O
3
4
Figure 1
OH
O
NEt2
O
NEt2
We wish to report another efficient route for the synthesis
of wrightiadione 1 by directed remote metalation
(DreM).4 Heteroatom-facilitated metalation has become
an increasingly important strategy in organic synthesis
and has been widely adopted in the functionalization of
both aromatic and heterocyclic systems.4,5
OH
O
H3C
OMe
O
5
7
6
Scheme 1
The lithiation of flavones and isoflavones has been suc-
cessfully used to introduce substituents by Dean’s group.6
Isoflavone was lithiated at position 2 but it did not react
easily; after carboxylation the yield of the 2-carboxylic
acid was low.6 In addition, it appeared not to react at all
with the lithium bistrimethylsilylamide reagent.
The lateral lithiation reaction10 of toluamide 7 using LDA
as base in THF at –78 °C followed by reaction with meth-
yl salicylate (6) provided 2-hydroxybenzoin 511 in 58%
yield as shown in Scheme 2. However, the tolyl anion 8
could also react with another molecule of 7 to give the
deoxybenzoin intermediate 9 which further lactonized to
isocoumarin12 10 (11%). Similar coupling of the anion of
methyl ortho-toluate to the corresponding isocoumarin
has been reported by Hauser.13
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1037,1039,ftx,en;U03503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1038
N. Thasana, S. Ruchirawat
LETTER
CH3
O
OH
O
O
NEt2
Li
O
LDA, THF
–78 °C
6
NEt2
NEt2
7
8
5 (58%)
7
Li
H3C
H
O
O
O
O
NEt2
9
10 (11%)
Scheme 2
Compound 5 was converted to the desired isoflavone15 4
in 48% yield accompanied by the spiro compound16 12 in
14% yield by reaction with a mixture of DMF–MeSO2Cl
and BF3·Et2O at 70 °C.14
Acknowledgment
We acknowledge the Thailand Research Fund (TRF) for the ge-
nerous support of our research program and the award of Senior Re-
search Scholar to S. R. as well as the award of the Royal Golden
Jubilee Scholarship to N. T. We also acknowledge the facilities in
the Department of Chemistry provided by the PERCH program.
The spiro lactone 12 was probably formed by autooxida-
tion at the benzylic position of deoxybenzoin 5 to produce
intermediate benzoin 11 which could further cyclize in a
tandem fashion to compound 12 as shown in Scheme 3.17
The lithiation of isoflavone 4 was carried out by using
LDA (5 equiv) in THF at –78 °C.18 The carbanion inter-
mediate 3 thus formed then reacted with the carboxamide
group to give the desired wrightiadione 1 in moderate
yield (49%). The identity of wrightiadione was proved by
comparison of the spectroscopic data with that of the pre-
viously synthesized product.2
References
(1) Lin, L.-J.; Topcu, G.; Lotter, H.; Ruangrungsi, N.; Wagner,
H.; Pezzuto, J. M.; Cordell, G. A. Phytochemistry 1992, 31,
4333.
(2) Ruchirawat, S.; Thasana, N. Synth. Commun. 2001, 31,
1765.
(3) Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43,
4515.
(4) (a) Clayden, J. Organolithiums: Selectivity for Synthesis,
Tetrahedron Organic Chemistry Series, Vol. 23; Baldwin, J.
E.; Williams, R. M., Eds.; Pergamon Press: Oxford, 2002.
(b) Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Green, L.;
Chauderr, B.; Snieckus, V. J. Heterocyclic Chem. 1999, 36,
1453. (d) Chauderr, B.; Green, L.; Snieckus, V. Pure Appl.
Chem. 1999, 71, 1521.
In conclusion, we have described an alternative approach
to the synthesis of wrightiadione 1 via a basic directed re-
mote metalation strategy. The synthesis is highly concise
and employs the rarely used isoflavone metalation.
O
OH
O
O
NEt2
O
O
O
NEt2
O
LDA, THF
–78 °C
DMF, MeSO2Cl
BF3·OEt2, 70 °C
O
4 (48%)
5
1 (49%)
[O]
O
OH
O
O
NEt2
O
O
O
O
12 (14%)
11
Scheme 3
Synlett 2003, No. 7, 1037–1039 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Wrightiadione
1039
(5) Gschwend, H. W.; Rodriguez, H. Org. React. 1979, 26, 9.
(6) Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.;
Varma, R. S. J. Chem. Soc. Perkin Trans. 1 1985, 799.
(7) Daia, G. E.; Gabbutt, C. D.; Hepworh, J. D.; Heron, B. M.;
Hibbs, D. E.; Hursthouse, M. B. Tetrahedron Lett. 1998, 39,
1215.
(8) (a) Wahala, K.; Hase, T. A. J. Chem. Soc. Perkin Trans. 1
1991, 3005. (b) Bass, R. J. J. Chem. Soc. Chem. Comm.
1976, 78.
(9) (a) Davis, S. E.; Church, A. C.; Griffith, C. L.; Beam, C. F.
Synth. Commun. 1997, 27, 2961. (b) Poindexter, G. S. J.
Org. Chem. 1982, 47, 3787.
(10) Reaction of N,N-diethyl-O-toluamide (7) with methyl
salicylate (6) in the presence of LDA: A solution of LDA in
dry THF (200 mL) was prepared by adding diiso-
8.0 Hz); 13C NMR (50 MHz, CDCl3) d 20.7, 105.9, 120.3,
125.8, 126.0, 128.2, 129.2, 129.5, 129.8, 131.0, 132.7,
134.8, 136.7, 137.5, 155.5, 162.6; MS (EI) m/z 236 (M+,
100), 208 (83), 207 (39), 193 (27), 179 (43) Anal. calcd. for
C16H12O2: C, 81.34; H 5.12. Found: C, 80.94; H 4.87.
(13) Hauser, F. M.; Rhee, R. P.; Prasanna, S.; Weinreb, S. M.;
Dodd, J. H. Synthesis 1980, 72.
(14) 3-(2-N,N-Diethylcarboxamidephenyl)-4H-chromen-4-one
(4). 2-Hydroxydeoxybenzoin (6, 0.62 g. 2.0 mmol) was
dissolved in distilled BF3·Et2O (5 mL) under argon. A
solution of methanesulfonyl chloride (3 mL) in dry DMF (15
mL) was slowly added and the mixture was heated at 70 °C
for 2 h. The reaction was cooled to room temperature and
poured into an ice-cold aq sodium acetate. The mixture was
extracted with ethyl acetate. The combined organic extracts
were washed with water and dried over anhydrous sodium
sulfate. Solvent was removed under vacuum and the residue
was purified by preparative layer chromatography on silica
gel (elution with CH2Cl2) to give isoflavone 4 as a white
solid (0.30 g, 48%).
(15) Compound 4: mp 173–175 °C (EtOH); IR (KBr) 1639
(C=O), 1595, 1471, 1386, 1359, 1299, 1228 cm–1; 1H NMR
(200 MHz, CDCl3) d 0.89 (m, 6 H), 3.04 (m, 4 H), 7.35 (m,
6 H), 7.63 (ddd, 1 H, J = 0.6 Hz, 1.2 Hz, 7.2 Hz), 7.57 (dd, 1
H, J = 1.2 Hz, 7.2 Hz), 7.61 (dd, 1 H, J = 1.6 Hz, 7.0 Hz, 8.6
Hz), 8.06 (s, 1 H), 8.18 (ddd, 1 H, J = 0.4 Hz, 1.6 Hz, 8.0 Hz);
13C NMR [50(16) MHz, CDCl3] d 12.1, 13.7, 38.5, 42.8,
118.2, 123.5, 124.2, 125.3, 126.0, 126.1, 128.3, 128.7,
131.4, 133.8, 137.5, 154.7, 156.3, 170.2, 176.2; MS (EI) m/
z 321 (M+, 13), 320 (24), 249 (100), 221 (55), 192 (6), 165
(25) Anal. calcd. for C20H19NO3: C, 74.75; H 5.96 N, 4.36.
Found: C, 74.95; H 5.54 N, 4.07.
(16) Compound 12: white solid (14%): mp 183–185 °C (EtOH);
IR (KBr) 1719 (C=O), 1649 (C=O) cm-1; 1H NMR (200
MHz, CDCl3) d 7.19 (m, 2 H), 7.33 (m, 1 H), 7.70 (m, 2 H),
7.78 (m, 2 H), 7.92 (m, 1 H); 13C NMR (50 MHz, CDCl3) d
104.2, 113.7, 118.6, 122.6, 123.6, 125.8, 126.2, 127.1,
132.0, 135.2, 139.8, 142.3, 167.0, 171.3, 192.6; MS (EI)
m/z 252 (M+, 62), 224 (41), 223 (23), 196 (26), 195 (15), 180
(100), 168 (37) Anal. calcd. for C15H8O4: C, 71.43; H 3.20.
Found: C, 71.74; H 3.10.
propylamine (14.7 mL, 0.10 mol) dropwise to a 0.95 M
solution of n-BuLi (95 mL, 0.10 mol) in hexane under argon
at 0 °C. The ice-water bath was replaced by a dry ice/acetone
bath. The stirring was continued for 30 min at –78 °C, and
then N,N-diethyl-O-toluamide (7, 14.4 g, 75.0 mmol) in dry
THF (30 mL) was added. The pale yellow solution turned to
deep red, indicating anion formation. The reaction mixture
was allowed to warm to 0 °C with an ice-water bath, stirred
for 10 min and the ice-water bath was replaced by a dry ice/
acetone bath. The stirring was continued for 1 h. A solution
of methyl salicylate (6, 11.4 g, 75.0 mmol) in dry THF (30
mL) was added slowly via syringe to the above mixture.
Stirring at this temperature was continued for 2 h and then
the reaction mixture was warmed to room temperature. 2 N
HCl was added and the entire mixture was stirred for 1 h.
Removal of solvent under reduced pressure gave a residue
which was extracted with CH2Cl2. The combined organic
extracts were washed with aqueous sodium carbonate
solution, water and brine solution, and dried over anhydrous
sodium sulfate. After removal of solvent, the residue was
column chromatographed on silica gel using EtOAc and
hexane as eluents to provide the desired 2-(2-N,N-diethyl-
carboxamidephenyl)-1-(2-hydroxyphenyl)ethan-1-one (5)
as the major adduct (13.5 g, 58%) and 3-(2-methylphenyl)
isochromen-1-one (10) as the minor adduct (1.9 g, 11%).
(11) Compound 5: colorless crystals: mp 168–169 °C
(EtOAc:hexane); IR (KBr) 3061 (OH), 1744 (C=O), 1648
(C=O), 1628, 1603, 1486, 1272, 1215 cm–1; 1H NMR (200
MHz, CDCl3) d 1.03 (t, 3 H, J = 7.2 Hz), 1.09 (t, 3 H, J = 7.2
Hz), 3.15 (q, 2 H, J = 7.2 Hz), 3.45 (m, 2 H), 4.44 (br s, 2 H),
6.95 (m, 2 H), 7.30 (m, 4 H), 7.47 (dd, 1 H, J = 1.2 Hz, 7.6
(17) Letcher, R. M.; Kwok, N.-C.; Lo, W.-H.; Ng, K.-W. J.
Chem. Soc. Perkin Trans. 1 1998, 1715.
(18) Wrightiadione 1: A solution of LDA in dry THF (10 mL)
was prepared as in ref.10 using diisopropylamine (0.4 mL,
2.6 mmol) and 0.7 M solution of n-BuLi (3.0 mL, 2.5 mmol)
in hexane. The LDA was stirred for 30 min at –78 °C, and
then isoflavone 4 (0.15 g, 0.5 mmol) in dry THF (5 mL) was
added. Stirring at this temperature was continued for 2 h and
then the reaction mixture was warmed to room temperature.
Water was added and the mixture was stirred for 30 min. The
organic layer was separated and washed again with water,
dried over Na2SO4, filtered, and evaporated under reduced
pressure. The resulting orange residue was purified by
preparative layer chromatography on silica gel using CH2Cl2
as eluent to give crystals of wrightiadione 1 (0.07 g, 49%).
Hz), 7.90 (dd, 1 H, J = 1.0 Hz, 8.1 Hz), 12.09 (s, 1 H); 13
C
NMR (50 MHz, CDC l3) d 12.1, 13.7, 38.5, 42.0, 42.8, 118.3,
119.0, 119.2, 125.6, 127.0, 128.9, 130.3, 131.2, 131.3,
136.6, 137.3, 162.4, 170.3 (CON), CO not observed; MS
(EI) m/z 311 (M+, 0), 238 (68), 210 (85), 181 (100), 152 (21).
HRMS (FAB) calcd for C19H21NO3 [MH+]: 312.1560; found
312.1560.
(12) Compound 10: white solid: mp 80–82 °C (EtOH); IR (KBr)
1719 (C=O), 1648 (C=O) cm–1; 1H NMR (200 MHz, CDCl3)
d 2.46 (s, 3 H), 6.56 (s, 1 H), 7.26 (m, 3 H), 7.46 (m, 3 H),
7.69 (dd, 1 H, J = 1.2 Hz, 7.2 Hz), 8.28 (dd, 1 H, J = 0.8 Hz,
Synlett 2003, No. 7, 1037–1039 ISSN 1234-567-89 © Thieme Stuttgart · New York