JOURNAL OF CHEMICAL RESEARCH 2009
MARCH, 151-153
RESEARCH PAPER 151
Conversion of 3-arylphthalides into anthrones with a methylcarbonyl
substituent at the C-10 position.
Adam Bieniek*, Monika M. Bartczak and Jan Epsztajn
Department of Organic Chemistry, Faculty of Chemistry, University of t6dt, 90-136 t6dt, Narutowicza 68, Poland
The ortho-lithiation
Reductive alkylation with 1-methoxy-1-trimethylsilyloxyethene
was cyclised to an anthrone bearing a methoxycarbonyl methylene unit at C-10.
of a benzoic acid anilide followed by condensation with an aryl aldehyde gave a 3-arylphthalide.
gave a substituted aromatic carboxylic acid which
Keywords: Mukaiyama reaction, benzoic acids, acetoacetic esters, 6-methyl-l,3-dioxin-4-one, anthrones
Recently there has been increased activity directed towards
the preparation of anthrones alkylated at the C-IO position.
~O,,-,:::
R '--1.
~"-':::
°OH
Some members of this family have been found in nature and
possess a variety of biological properties.I•S For example it
has been observed that anthrones bearing alk1 and carbonyl
substitutents at C-IO are potent inhibitors of leukotriene
B4 biosynthesis. I A compound with an acetic acid methyl
ester connected to the C-IO carbon atom was isolated from
Rubus ulmifolius and showed antimicrobial activity against
Staphylococcus aureus.4 Our attention has been focused
on obtaining a synthetic methodology leading to anthrone
derivatives in which a methylcarbonyl group is attached to the
C-IO position.
Consequently, we now report an efficient strategy for the
transformation of aromatic carboxylic acids A into the desired
anthrones B (as is depicted in Scheme 1) in three steps,
starting from the benzoic acid anilides 1.
Recently we have reported6 that a secondary carboxamide
moiety provides an excellent possibility for a regioselective
synthesis of 3-arylphthalides, which are the key starting
materials here.
I
- R 2
' -'~
R
--
I
~
~
--
o
B
R3
A
R' = -OMe or -H
R2 = -OMe or -H
R3 = Me or -OMe
Scheme 1
OMe
==<
OSiMe3
4
3
Fig. 1
3-Arylphthalides 2 were obtained by the lithiation of benzoic
acids anilides 1 using n-BuLi in THF7,8 followed by the
reaction of the resultant bis(N-and C-ortho)lithiated anilides
with aromatic aldehydes. The ortho-hydroxymethylated
anilides which were formed gave the corresponding phthalides
2 (Scheme2) as a result of acid-catalysed cyclisation.
In the following step the phthalides 2 were reductively
alkylated at the C-3 position by reaction with I-methoxy-
I-trimethylsilyloxyethene (3) or 2,2-dimethyl-6-methylene-
4-trimethoxysilyloxy-4H-[ 1,3]diox-4-ene (4) (Fig. 1) in
the presence of TiCl4 (Mukaiyama reaction conditions9,IO).
In the first case, the esters Sa, 5b were formed.? On the
other hand, reaction of the phthalide 2 with compound
4 gave the corresponding dioxins 6 which on hydrolysis
in boiling toluene furnished the ketones 5c, 5d and Sell
(Scheme 2).
Experimental
M.p.s were determinedusing a Boetiushot-stageapparatusandthey
are uncorrected.IR spectrawere recordedon a NEXUSFT-IR(KEr
pellets). NMR analyses were performed on a Varian-Gemini-200
(200 MHz) using TMS as an internal standardin CDCI3;chemical
shifts are quoted in ppm. Compoundswere purifieduntil observed
as singlespotson TLC (KieselgelGF-254type 60). Tetrahydrofuran
was distilled before use from sodium-benzophenoneketyl, and
dicWoromethanewas driedovermolecularsieves,3A. Othersolvents
and reagentswere purified accordingto standardprocedureswhere
appropriate. n-Butyllithium(n-BuLi) (Aldrich) was titrated before
use. Reaction temperatures were recorded as bath temperatures.
Elemental analysis was carried out by the Centre of Molecular
and MacromolecularStudies, Polish Academy of Sciences, L6di.
Compounds5a-c and5ewere obtainedby knownmethods,?,ll
4-Methoxy-2-{l-(2-methoxyphenyl}-3-oxobutyl}-benzoic
Acid (5d):
A solutionof 0.01mol of acid 6 in 20 cm3of tolueneand 10cm3of
waterwas heatedto boilingfor 12h. Themixturewas extractedwith
chloroform(3 x 20cm3).Thenthecombinedextractswereevaporated
to dryness,crudeproducts5d waspurifiedby crystallisation.
Yield 68%; M.p. 139-140°C (white needles from diisopropyl
ether/ethylacetate/hexane6:2:I); IR (KEr): 1709,1684,cm-' (C=O);
'H NMR (CDCI3)7.89-7.85 (m, 1H,ArH), 7.26-7.19 (m, 2H,ArH),
6.80-6.66 (m, 4H, ArH), 5.72 (t, 1H,J= 7.0 Hz, CH), 3.74 (s, 3H,
OMe), 3.71 (s, 3H, OMe), 3.36 (dd, 1H,J, = 8.7 Hz, J2 = 17.0Hz,
CH2),3.15(dd, 1H,J, = 7.1Hz,J2 = 17.0Hz, CH2),2.19(s, 3H,Me);
l3CNMR (CDCI3)209.3, 170.7, 162.2, 156.8, 146.3, 133.1, 130.9,
127.9,126.5,120.3,114.6,110.6,110.5,55.2,49.1,35.3,29.6. Anal.
Calcdfor C19H200SC:, 69.50;H, 6.09.Found:C, 69.60;H, 6.01%.
It was anticipated that treatment of the compounds (5),
with trifluoroacetic acid anhydride (TFAA) (Friedel-Crafts
cyclisationl2) would provide an effective route to the desired
CIO-substituted anthrones 7. In practice, compounds 5 when
treated with TFAA in methylene chloride produced the
corresponding anthrones 7 in satisfactory yield (Scheme 2).
The IR and proton NMR data indicated that the compounds
which were formed were pure keto-forms. No enols were
detected.
In conclusion, we have developed
a novel general
strategy for the preparation of CIO-substituted anthrones.
The procedure is useful particularly because of its efficiency,
the ready availability of the starting materials and the ease of
operation.
Cyclisation of compounds 5 using trifiuoroacetic acid anhydride;
general procedure
Tothe stirredsolutionof acids5 (0.01mol) in 10cm3ofCH2CI2was
addedofTFAA at O°C.The mixturewas stirredfor 10-72 h at room
temperature.Next, the solvent was evaporatedin vacuo and crude
Bieniek, Adam
