The synthesis of kermesic acid by acetylation-aided tautomerism of 6-chloro-2,5,8-trihydroxynaphtho-1,4-quinone

Article abstract of DOI:10.1016/j.tet.2008.02.018

Methodology has been sought towards obtaining a 2-chloro-1,4-naphthoquinone bearing hydroxyl groups in the adjoining ring for obtaining either kermesic or carminic acids. In the first of these objectives, kermesic acid has been synthesised from 6-chloro-2,5,8-trihydroxynaphtho-1,4-quinone by the regioselective cycloaddition of the 1,2-diacetate formed by its acetylation-aided tautomerism and cycloaddition with (E)- and (Z)-3-alkoxycarbonyl-2,4-bis(trimethylsilyloxy)penta-1,3-dienes. The parent unacetylated quinone resists cycloaddition.

Full text of DOI:10.1016/j.tet.2008.02.018

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3471e3476
www.elsevier.com/locate/tet
The synthesis of kermesic acid by acetylation-aided tautomerism of
6-chloro-2,5,8-trihydroxynaphtho-1,4-quinone
Steve J. Bingham a,b, John H.P. Tyman a,b,
*
a Department of Chemistry, Brunel University, Uxbridge, Middlesex UB8 3PH, UK
b Laboratories of European Colour plc, Nathan Way, London SE18, UK
Received 19 November 2007; received in revised form 4 February 2008; accepted 7 February 2008
Available online 9 February 2008
Abstract
Methodology has been sought towards obtaining a 2-chloro-1,4-naphthoquinone bearing hydroxyl groups in the adjoining ring for obtaining
either kermesic or carminic acids. In the first of these objectives, kermesic acid has been synthesised from 6-chloro-2,5,8-trihydroxynaphtho-1,4-
quinone by the regioselective cycloaddition of the 1,2-diacetate formed by its acetylation-aided tautomerism and cycloaddition with (E)- and (Z)-
3-alkoxycarbonyl-2,4-bis(trimethylsilyloxy)penta-1,3-dienes. The parent unacetylated quinone resists cycloaddition.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Carminic acid 2, is an abundant indigenous but expensive
product from Peru, Mexico and the Canary Islands, and his-
torically superseded kermesic acid through its brilliant red
hues, although dyeing with kermes is still practised.5 By con-
trast, the natural European source of kermesic acid from the
insect Kermes illicis, which infects the kermes oak is not
widespread. Thus, it was of interest to devise a synthesis
that could provide a tricyclic intermediate capable of obtain-
ing either kermesic or carminic acid, which did not contain
a halogeno group that is hydrolysed with difficulty as in pre-
Kermesic acid 1a is the red colourant component of
kermes, a dyestuff of great antiquity and most probably the
earliest for which records exist.1 Kermesic acid is the aglycone
of carminic acid 2, the colourant principle of cochineal.2 A
preliminary communication3 has appeared and the isomer, iso-
kermesic acid, 1-methyl-3,5,7,8-tetrahydroxyanthra-9,10-qui-
none-2-carboxylic acid, has been synthesised.4
cursors
respectively.
A and B
involved in previous syntheses,6,7
O
OH
OH
Me
O
OH
Me
OR
R1O2C
RO
O
HO2C
HO
OH
OH
OR HO
A
B
Me
O
OMe
O
Me
OMe
Br
O
O
OH
OR
MeO2C
MeO2C
MeO
1
2
Cl
OMe
MeO
OMe
O
O
1a R = R1= H
b R = H, R1 = Me
Therefore, effort was directed towards the preparation of
2-halogeno-5,6,8-trihydroxynaphtho-1,4-quinone 3 (form 2),
which, like naphthazarins in general, could exist as the tauto-
mers 3 (forms 1 and 2) and contain the prerequisite hydroxyl at
positions 2 (form 2) and 6 (form 1). The halogen at 2-position
(form 2) would serve to both direct DielseAlder addition in
the correct manner and facilitate aromatisation to the required
anthraquinone at the next stage.
c R = R1 = Me
Formulae 1 and 2
* Corresponding author.
E-mail address: jhptyman@hotmail.com (J.H.P. Tyman).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.018

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S.J. Bingham, J.H.P. Tyman / Tetrahedron 64 (2008) 3471e3476
2. Results and discussion
The starting point of the synthesis (Scheme 1), 3-chloro-2-
hydroxy-5-methoxyacetophenone 4 was prepared as for the
bromo analogue8 in 80% yield by selective chlorination of
2-hydroxy-5-methoxyacetophenone with N-chlorosuccinimide
(NCS) in acetic acid containing Mg(OAc)2. Methylation of 4
with dimethyl sulfate in acetone containing potassium carbon-
ate afforded 5 (X¼Cl) in 81% and 5 (X¼Br) in 82% yield. Re-
action of the respective acetophenones with dimethyl
carbonate in methanolic sodium methoxide gave the b-ketoest-
ers 6 in quantitative yields, which upon treatment with oxalyl
chloride in nitromethane containing anhydrous aluminium
chloride, a method used previously for unhalogenated naph-
thoquinones,9 afforded the two 3-methoxycarbonyl-6-halo-
Figure 1. X-ray crystal structure of 6-chloro-2,5,8-trihydroxynaphtho-1,4-qui-
˚
˚
none; CeOH: au, a2, a3¼1.33, 1.34, 1.35 A; C]O: bu, b2¼1.22, 1.24 A.
to the 5-position in form 2 may possibly occur enabling the
more susceptible 6-OH to subsequently react. Such a mecha-
nism may explain non-acetylation of the hydrogen-bonded
8-OH. There is no further information currently available
to support this hypothesis. An X-ray structure determination
geno-2,5,8-trihydroxynaphtho-1,4-quinones
7
(X¼Br) in
48% and 7 (X¼Cl) in 56% yields, respectively, together
with some partially demethylated material. Hydrolysis of the
trihydroxyquinone esters with either aqueous sodium hydrox-
ide followed by acidification or preferably with hot acetic acid
containing hydrochloric acid gave 3 (X¼Cl) in 53% yield and
the bromo analogue in 69% yield. Under a variety of condi-
tions 3 (X¼Cl) failed to undergo DielseAlder cycloaddition
with the dienes (E)- and (Z)-3-methoxycarbonyl-2,4-bis(trime-
thylsilyloxy)penta-1,3-dienes 8a. This was attributed primarily
to intramolecular hydrogen bonding of the 2-OH group10 thus
inhibiting tautomerism of the naphthazarin system and locking
the structure in form 1.
of 3-chloro-5,6-diacetoxy-8-hydroxynaphtho-1,4-quinone
(Fig. 2) provided definitive confirmation of its structure.
OH
8
O
OH
O
4
5
1
Cl
6
7
Cl
3
2
7
2
3
OH
OH
6
4
5
OH
O
8
OH
1
O
3
(
Form 1)
3
(Form 2)
OH
Support for this exclusive formulation was provided physi-
cally by an X-ray structure determination (Fig. 1), and chem-
ically by (a) its ready Michael addition under mild conditions
at the 3-position with (E)- and (Z)-3-ethoxycarbonyl-3-penten-
2-ones to give 13, and (b) selective O-methylation in 77%
yield at the 2-position with BF3$MeOH, the product of which
removed the impediment to tautomerism and facilitated
cycloaddition.
Acetylation of 3 in dichloromethane with pyridine/acetic
anhydride afforded triacetoxy compounds in 91% yield as
a 2:1 mixture (from NMR analysis) of 6-chloro-2,3,8-triace-
toxynaphtho-1,4-quinone and 2-chloro-5,6,8-triacetoxynaph-
tho-1,4-quinone. However, heating 3 with acetic anhydride
alone at 100 ꢀC afforded the 2-chloro-5,6-diacetoxy com-
pound (9, R¼R0¼Ac) in quantitative yield. It is postulated
(Scheme 2) that acetylation of the 2-OH group occurs first al-
lowing tautomerism to give form 2, which is then followed by
acetylation at the 5-position thus locking the structure to that
form. It is conjectured that since hydrogen-bonded OH groups
are more difficult to acetylate, migration of the 6-acetyl group
O
O
O
OH
OH
OH
O
O
Cl
Cl
Cl
i
OH
ii
OAc
OAc
OH
(form 2)
O
OAc
9
3 (form 1)
Scheme 2. Reagents and conditions: (i) Ac2O, 100 ꢀC, 3 h; (ii) vacuum to
dryness.
The diacetoxy compound readily underwent cycloaddition
with (E)- and (Z)-3-methoxycarbonyl-2,4-bis(trimethylsilyl-
oxy)penta-1,3-dienes 8a followed by aromatisation in boiling
toluene to afford 10, methyl 5,6-diacetoxy-3,8-dihydroxy-1-
methylanthra-9,10-quinone-2-carboxylate in 87% yield after
column chromatography. Definitive proof of structure was
provided by an X-ray structural study (Fig. 3). The isopropyl
analogue 8b reacted similarly in 64% yield to give 12b.
2-Chloro-6-methoxy-5,8-dihydroxynaphtho-1,4-quinone 11,
in which normal naphthazarin tautomerism is able to operate
O
O
OMe
OMe
OH
OMe
OH
OH
O
OH
O
O
O
O
X
X
X
X
OMe
OMe
3
iv
iii
ii
i
OH
OMe
OMe
OMe
O
4
5
6
7
Scheme 1. Reagents and conditions: 4 (X¼Cl) (i) NCS, HOAc, Mg(OAc)2, rt, 24 h; DMS, Me2CO, K2CO3, heat, 24 h; (ii) NaOMe, MeOH, (MeO)2CO, heat; (iii)
(COCl)2, MeNO2, AlCl3, 0e80 ꢀC, 3 h; (iv) 10% concd HCleHOAc, 100 ꢀC, 5 h.

S.J. Bingham, J.H.P. Tyman / Tetrahedron 64 (2008) 3471e3476
3. Experimental
3473
3.1. Spectroscopy
Infrared spectra in the range 600e4000 cmꢁ1 were ob-
tained on a PerkineElmer 1420 spectrophotometer and elec-
tronic spectra in the range 200e600 nm were recorded on
a PerkineElmer Lambda 9 spectrophotometer. 1H NMR spec-
tra in deuterated solvents, with Me4Si as internal standard,
were obtained on Varian T 60, CFT 20 and JEOL FX 200 in-
struments at 60, 80 and 200 MHz, respectively (J values are
1
given in hertz). When necessary, 13C and high resolution H
NMR spectra were obtained at 400 MHz through the SERC
facility, on a Bruker WM 400 at the University of Warwick.
Low resolution EIMS were obtained on a modified AEI
MS902 and high resolution, FAB spectra and accurate mass
determinations through the SERC facility at University of
Wales, Swansea.
Figure 2. X-ray crystal structure of 2-chloro-5,6-diacetoxy-8-hydroxynaphtho-
1,4-quinone.
(although the structure is not locked as with the diacetate), also
underwent cycloaddition with the diene 8a in boiling toluene to
give after work-up methyl 6-methoxy-3,5,8-trihydroxy-1-meth-
ylanthra-9,10-quinone-2-carboxylate 12a in 42%yield. This
observation is consistent with the previously observed2 cyclo-
addition of 2-chloronaphthazarin with diene 8a.
Possibly forms of both type 1 and 2 are present with the
methoxy compound 11 since there is no locking of the struc-
ture in this compound.
Hydrolysis of 10 in 1% methanolic sodium carbonate fol-
lowed by acidification gave methyl kermesate 1b in quantita-
tive yield, and hence by refluxing in acetic acid containing
hydrochloric acid, kermesic acid was derived (Scheme 3).
Methylation of methyl kermesate 1b with dimethyl sulfate in
acetone solution containing potassium carbonate gave methyl
3,5,6,8-tetramethoxy-1-methylanthraquinone-2-carboxylate 1c,
which was identical with an authentic sample kindly made
available by Prof. P. Brassard.
It is believed that 3 has the potential to facilitate access to
carminic acid. For this, 3 (form 1) appears to be an ideal can-
didate by way of Michael and enamine reactions from initial
work. Such chemical approaches using kermesic acid itself
as an intermediate to carminic acid have not, so far, been suc-
cessful although this or xanthokermesic are the likely biosyn-
thetic precursors.
3.2. Chromatography
Analytical TLC was achieved on commercial plates (Cam-
lab 0.25 mm) and fluorescent indicator UV254nm. Kieselgel 60
(Merck, 40e60 mm) was used for flash chromatography and
Merck silica gel 7734 for gravity columns. GLC was carried
out with a HewlettePackard 402 chromatograph with FID,
glass columns (152 cmꢂ2.5 mm id) containing 100e120
BSS mesh acid washed Celite and the stationary phase
OV17 at 200 ꢀC with nitrogen as carrier gas.
3.3. General
Melting points were recorded with an electrothermal digital
melting point apparatus and are uncorrected. Elemental analy-
ses were carried out by Medac Ltd., Brunel University; Butter-
worth Laboratories, Teddington and NRM Ltd., Bracknell,
Berks. Solvents and reagents were purified (where necessary)
by standard techniques. Intermediates were obtained from Al-
drich Chemical Co. X-ray measurements were effected at the
National Crystallographic Service, now at University of
Southampton.
3.4. Synthesis of kermesic acid
(E)- and (Z)-3-methoxycarbonyl-2,4-bis(trimethylsilyloxy)-
penta-1,3-dienes, and (E)- and (Z)-3-isopropoxycarbonyl-2,4-
bis(trimethylsilyloxy)penta-1,3-dienes were prepared as
described.2,4
3.4.1. 3-Chloro-2-hydroxy-5-methoxyacetophenone (4, X¼Cl)
To a stirred solution of magnesium acetate prepared by
dissolving magnesium turnings (4.86 g, 0.20 mol) in glacial
acetic acid (300 cm3), 2-hydroxy-5-methoxyacetophenone
(33.24 g, 0.250 mol) was added followed 10 min later by N-
chlorosuccinimide (33.24 g, 0.250 mol). After 24 h at ambient
temperature the brown solution was poured into crushed ice
(1250 g) and water (1250 cm3) and the precipitate filtered,
Figure. 3. X-ray crystal structure of methyl 5,6-diacetoxy-3,8-dihydroxy-1-
methylanthra-9,10-quinone-2-carboxylate.

3474
S.J. Bingham, J.H.P. Tyman / Tetrahedron 64 (2008) 3471e3476
Me
O
OH
O
O
Me
OMe
Br
OMe
OMe
O
O
Me
Cl
MeO2C
MeO
MeO2C
MeO
CO2Et
OH
Cl
OMe
O
OH
O
A
13
B
O
O
OH
O
O
Me
OH
OTMS
OTMS
R2O2C
HO
Me
R2O2C
Cl
+
ii
OR
iii
i
1a
OR
OR1
OR1
10 R = R1= Ac, R2= Me
12a R = R2= Me. R = H
b R = Me, R2= Pri,R1 = H
9 R = R1= Ac
11 R = Me,R1= H
8a R2= Me
R2= Pri
b
Scheme 3. For 1a and 1b. Reagents and conditions: 9 (i) toluene, 8a heat, 24 h, column chromatography, SiO2; (ii) MeOH, 1% Na2CO3; (iii) HOAceHCl, heat; (iv)
for 1c, DMS, Me2CO, K2CO3, heat. Compound 11 from 3, with BF3$MeOH; toluene, 8, heat, column chromatography SiO2.
washed with water and air dried to give a green-brown solid
(32.10 g, 80%), which crystallised (ethanol) as green-yellow
needles, mp 78e79 ꢀC (Found: C, 54.11; H, 4.59. C9H9ClO
requires C, 53.88; H, 4.52%.). dH (80 MHz, CDCl3) 2.61 (3H,
s, CH3CO), 3.77 (3H, s, 5-CH3O), 7.12 (1H, s, 4-H), 7.16 (1H,
s, 6-H), 12.24 (1H, s, 2-OH); m/z 202 (Mþ, 29%), 200 (Mþꢁ2,
87%), 185 (100), 18 (11).
3.4.4. 3-Bromo-2,5-dimethoxyacetophenone (5, X¼Br)
3-Bromo-2-hydroxy-5-methoxyacetophenone
(24.51 g,
0.10 mol) treated as for the chloro compound gave the titled
product as a clear oil (21.25 g, 82%), bp 110e114 ꢀC/
0.5 mm Hg, mp 41e42 ꢀC. dH (80 MHz CDCl3) 2.62 (3H, s,
COCH3), 3.77 (3H, s, 2-OMe), 3.80 (3H, s, 5-OCH3), 7.04
(1H, d, J 3 Hz, H-4), 7.21 (1H, d, J 3 Hz, H-6); m/z Mþ found,
79
257.9892. Required for C10H BrO3, 257.9892.
11
3.4.2. 3-Bromo-2-hydroxy-5-methoxyacetophenone (4, X¼Br)
To a stirred mixture of 2-hydroxy-5-methoxyacetophenone
(22.24 g, 0.20 mol) and sodium acetate (17.25 g, 0.21 mol) in
glacial acetic acid (500 cm3), a solution of bromine (33.24 g,
0.21 mol) in glacial acetic acid (340 cm3) was added dropwise
for over 2 h. After 48 h at ambient temperature the brown so-
lution was added to crushed ice (1250 g) and water (1250 cm3)
and the precipitated product collected, washed with water and
dried to give a green solid (42.64 g, 87%), which crystallised
(ethanol) to afford green/yellow needles, mp 74e77 ꢀC (lit.8
76e76.5 ꢀC). dH (80 MHz, CDCl3) 2.62 (3H, s, CH3CO), 3.78
(3H, s, 5-CH3O), 7.16 (1H, d, J 3 Hz, 4-H), 7.35 (1H, d, J
3 Hz, H-6), 12.36 (1H, s, 2-OH).
3.4.5. Methyl 3-(3-chloro-2,5-dimethoxyphenyl)-3-
oxopropionate (6, X¼Cl)
With rapid stirring under nitrogen, 3-chloro-2,5-dimeth-
oxyacetophenone (21.46 g, 0.10 mol) in dimethyl carbonate
(90 cm3) was added dropwise to a solution of sodium methox-
ide from sodium (8.46 g, 0.37 mol) in dry methanol (81 cm3),
and the mixture was refluxed with removal of methanol via
a fractionating column. After 3 h, the mixture, cooled to ambi-
ent temperature, was treated with acetic acid (27 cm3) in
diethyl ether (90 cm3) followed by water (200 cm3). The sep-
arated organic phase was dried (magnesium sulfate), filtered
and concentrated in vacuo to give a light brown oil (27.3 g,
100%). dH (80 MHz, CDCl3) 3.72 (3H, s 2-OMe), 3.76 (3H,
s, 5-OMe), 3.82 (3H, s, CH3OCO), 3.99 (2H, s, OCCH2CO),
7.07 (2H, s, 4-H, 6-H); m/z 274 (Mþ 20%), 272 (Mþꢁ2, 59%).
3.4.3. 3-Chloro-2,5-dimethoxyacetophenone (5, X¼Cl)
To 3-chloro-2-hydroxy-5-methoxyacetophenone (20.06 g,
0.10 mol) in dry acetone (200 cm3) containing potassium car-
bonate (27.64, 0.20 mol), dimethyl sulfate (15 cm3 20.0 g,
0.16 mol) was added at ambient temperature and the mixture
refluxed for 24 h, after which it was cooled, poured into water
(5000 cm3). After 2 h, the above mixture was extracted with
dichloromethane (200 cm3), the extract dried, filtered, and
the filtrate evaporated to afford a clear oil, which was distilled
(bp 91 ꢀC/0.1 mm Hg) to give a solid upon refrigeration. dH
(80 MHz, CDCl3) 2.60 (3H, s, CH3CO), 3.80 (3H, s, 2-OMe),
3.82 (3H, s, 5-OMe), 6.99, 7.00 (2ꢂ1H, 2s, 4-H, 6-H); m/z 216
(Mþ, 27%), 214 (Mþꢁ2, 79%).
3.4.6. Methyl 3-(3-bromo-2,5-dimethoxyphenyl-3-
oxopropionate (6, X¼Br)
3-Bromo-2,5-dimethoxyacetophenone treated as for the
chloro compound gave the titled product as a light brown oil
(31.7 g, 100%), which was used directly. dH (60 MHz, CDCl3)
3.72 (3H, s 2-OMe), 3.77 (3H, s, 5-OMe), 3.80 (3H, s,
CH3OCO), 4.00 (2H, s, OCCH2CO), 7.1e7.3 (2H, m, H-4
and H-6); m/z 318 (Mþ, 89%), 316 (Mþꢁ2, 88%), 286 (56),
285 (20), 261 (24), 260 (24), 259 (23), 258 (30), 256 (20),

S.J. Bingham, J.H.P. Tyman / Tetrahedron 64 (2008) 3471e3476
3475
246 (23), 245 (96), 244 (29), 243 (100), 241 (27), 230 (32),
228 (34), 165 (21), 58 (28), 43 (51), 18 (23).
7.51 (1H, s, 7-H), 11.27 (1H, s, 2-OH, exch. D2O), 13.33
(2H, br s, 5- and 8-OH, exch. D2O).
3.4.7. Methyl 6-chloro-2,5,8-trihydroxynaphtho-1,4-
quinone-3-carboxylate (7, X¼Cl)
3.4.10. 2-Chloro-5,6-diacetoxy-8-hydroxynaphtho-1,4-
quinone (9)
To a stirred solution of aluminium chloride under nitrogen
(4.00 g, 0.003 mol) in dry nitromethane (10 cm3) at 0 ꢀC,
6-Chloro-2,5,8-trihydoxynaphtho-1,4-quinone
(1.16 g,
5.0 mmol) in acetic anhydride (10 cm3) was heated at 120 ꢀC
for 5 h and then evaporated to dryness in vacuo to give a solid
(1.63 g, 100%), which crystallised (ethanol) as flat orange plates,
mp 168e171 ꢀC. dH (80 MHz, CDCl3) 2.36, 2.39 (2ꢂ3H, 2s,
2CH3CO), 6.78 (1H, s, 7-H), 7.43 (1H, s 3-H), 12.92 (1H, s,
OH, exch. D2O); m/z 326 (Mþ, 14%), 324 (Mþꢁ2, 32%).
methyl
3-(3-chloro-2,5-dimethoxyphenyl)-3-oxopropionate
(2.71 g, 0.01 mol) was added followed by oxalyl chloride
(0.82 cm3, 0.01 mol) and the mixture kept at 0 ꢀC for 1 h. It
was then allowed to rise to ambient temperature and heated
at 80 ꢀC for 1 h after which the cooled dark violet solution
was treated with 5% aqueous oxalic acid and extracted with
dichloromethane (3ꢂ100 cm3). The combined extracts were
washed with 5% sodium carbonate solution (150 cm3) and
the aqueous layer first washed with diethyl ether, before care-
ful acidification with concentrated hydrochloric acid to liber-
ate the product, which was extracted with dichloromethane
(3ꢂ100 cm3). The total extracts were dried (magnesium sul-
fate), filtered and concentrated to afford a dark red solid
(1.67 g), which (by TLC) contained some partially methylated
material, in addition to the desired product. Crystallisation
(toluene) gave fine dark red needles, mp 200e212 ꢀC (sub-
limes). dH (80 MHz, CDCl3) 4.05 (3H, s, CH3OCO), 7.35
(1H, s, 7-H), 12.01 (1H, s, 8-OH, exch. D2O), 13.48 (1H, s,
5-OH, exch. D2O); m/z 300 (Mþ, 10%), 298 (Mþꢁ2, 28%),
268 (20), 266 (56), 242 (21), 240 (78), 238 (46), 212 (12),
210 (16), 205 (12), 199 (17), 170 (19), 142 (14), 120 (13),
118 (13), 87 (35), 85 (100), 83 (100), 69 (21), 58 (58), 53
(27), 47 (13), 43 (15).
3.4.11. Methyl 5,6-diacetoxy-3,8-dihydroxy-1-methylanthra-
9,10-quinone-2-carboxylate (10, R¼R1¼Ac, R2¼Me)
A stirred solution of 2-chloro-5,6-diacetoxy-8-hydroxy-
naphtho-1,4-quinone under nitrogen (0.56 g, 1.70 mmol)
with (E)- and (Z)-3-methoxycarbonyl-2,4-bis(trimethylsilyl-
oxy)-penta-1,3-dienes (0.79 g, 2.50 mmol) in dry toluene
(19 cm3) was refluxed for 24 h and the mixture then evapo-
rated to dryness. The residue was purified by column chroma-
tography on silica gel (chloroform) to give a yellow-brown
solid (0.63 g, 87%), which crystallised (ethanol) as brown
prisms, mp 197e200 ꢀC. dH (80 MHz, CDCl3) 2.34, 2.43 (2ꢂ
3H, 2s, 2CH3CO2), 2.95 (3H, s, 1-CH3), 4.05 (3H, s, 2-
CH3OC]O), 7.17 (1H, s, 7-H), 7.68 (1H, s, 4-H), 10.43 (1H,
s, 3-OH, exch. D2O), 13.30 (1H, s, 8-OH, exch. D2O); m/z 428
(Mþ, 21%), 386 (53), 345 (23), 344 (83), 313 (46), 312 (100),
85 (28), 43 (59), 18 (77).
3.4.12. Methyl 3,5,6,8-tetrahydroxy-1-methylanthra-9,10-
quinone-2-carboxylate (methyl kermesate) (1b)
3.4.8. Methyl 6-bromo-2,5,8-trihydroxynaphtho-1,4-
quinone-3-carboxylate (7, X¼Br)
To methyl 5,6-diacetoxy-3,8-dihydroxy-1-methylanthra-
9,10-quinone-2-carboxylate (50 mg, 0.120 mmol) in methanol
(5 cm3) was slowly added 1% aqueous sodium carbonate solu-
tion and after 2 h, the purple red solution was carefully acidi-
fied with hydrochloric acid to give an orange precipitate,
which was filtered, washed with water, dried to give a solid
(40 mg, 100%), and crystallised (ethanol) to afford dark red
rhomboids, mp 240e241 ꢀC. dH (80 MHz, (CD3)2SO), 2.51
(3H, s, 1-Me), 3.89 (3H, s, MeOCO), 6.71 (1H, s, 7-H), 7.73
(1H, s, 4-H), 11.49 (1H, s, 3-OH, exch. D2O), 13.69 (1H, s,
8-OH, exch. D2O); m/z 344 (Mþ 59%), 313 (33), 312 (80),
284 (24), 58 (47), 44 (28), 43 (100), 18 (100).
From methyl 3-(3-bromo-2,5-dimethoxyphenyl)-3-oxopro-
pionate (3.17 g, 0.01 mol) treated as for the chloro analogue,
the title compound was obtained (together with some partially
demethylated material) as fine dark red needles, after crystal-
lisation (toluene), mp 190 ꢀC (decomp.). Found, Mþ
341.9375. Required for C12H7BrO7, 341.9375. dH (60 MHz,
CDCl3) 4.00 (3H, s, CO2 CH3), 7.58 (1H, s, H-7), 11.97 (1H,
s, 8-OH, D2O exch.); m/z 344 (Mþ, 8%), 342 (Mþꢁ2, 10%),
312 (36), 310 (35), 286 (82), 284 (100), 282 (27), 266 (19),
256 (25), 240 (35), 58 (30), 44 (37), 43 (91), 18 (24).
3.4.9. 6-Chloro-2,5,8-trihydroxynaphtho-1,4-quinone
(3, form 1)
3.5. Kermesic acid
Methyl 6-chloro-2,5,8-trihydroxynaphtho-1,4-quinone-3-
carboxylate (1.49 g, 5.0 mmol) in acetic acid (12 cm3) con-
taining concd hydrochloric acid (1.2 cm3) was heated at
100 ꢀC for 5 h. The mixture was cooled, poured into water
(500 cm3), extracted with dichloromethane (100 cm3), the
extracts dried (magnesium sulfate) and concentrated in vacuo
to give a red-black prisms (0.72 g, 53%), which crystallised
(xylene) to afford red-black prisms, mp 202e205 ꢀC (Found:
C, 50.20; H, 1.95. C10H5ClO5 requires, C, 49.89; H, 2.08.).
Mþ, found, 239.9829, 241.9790. C10H5ClO5 requires,
239.9826, 241.9796. dH (80 MHz, CDCl3) 6.34 (1H, s, 3-H),
1-Methyl-3,5,6,8-tetrahydroxy-9,10-dioxo-9,10-dihydro-
anthracene-2-carboxylic acid was obtained by alkaline hydro-
lysis under stronger conditions, followed by acidification. The
product was characterised as the tetramethyl ether.
3.5.1. Methyl 3,5,6,8-tetramethoxy-1-methylanthra-9,10-
quinone-2-carboxylate (1a, R¼R0¼Me)
To a suspension of methyl 3,5,6,8-tetrahydroxy-1-methyl-
anthra-9,10-quinone-2-carboxylate (25 mg, 0.073 mmol) in
dry acetone (10 cm3) containing potassium carbonate

3476
S.J. Bingham, J.H.P. Tyman / Tetrahedron 64 (2008) 3471e3476
(1.00 g, 7.3 mmol) dimethyl sulfate (0.50 cm3, 0.67 g,
5.3 mmol) was added and the mixture refluxed for 24 h. The
cooled mixture was poured into ice-cold water (100 cm3)
and extracted with dichloromethane (30 cm3), the extract
dried, concentrated and the brown solid chromatographed on
silica gel (chloroform) to give a yellow solid (26 mg, 89%),
mp 196 ꢀC and mixed mp 196 ꢀC (lit.6 Brassard); Rf 0.60 (sil-
ica gel, chloroformeethyl acetate). dH (80 MHz, CDCl3) 2.63
(3H, s, 1-Me), 3.93e3.96 (12H, 4s, 4OMe), 3.97 (3H, s, 2-
MeOC]O), 6.76 (1H, s, 7-H), 7.50 (1H, s, 4-H); m/z 401
(MþþH, 26%), 400 (Mþ, 100%), 386 (47), 385 (77), 383
(26), 371 (64), 369 (25), 354 (24), 353 (23), 339 (21).
s, CH3CO), 4.1e4.5 (4H, 2q and d, CH3CH2OCO, 1-H and 2-
H, J 7 Hz), 7.31 (1H, s, 7-H), 11.30 (1H, s, 8-OH, exch. D2O);
m/z 398 (Mþ, 66%), 352 (26), 351 (35), 350 (53), 308 (56),
268 (31), 266 (68), 238 (26), 233 (38), 58 (30), 43 (100), 18 (40).
3.6. Crystal data
Compound 3: C29H10Cl2O10 (reported as dimeric in X-ray
examination), M 479.16, triclinic, space group PI, a¼
3
˚
˚
˚
˚
6.756(4) A, b¼9.329(7) A, c¼11.536(9) A, V¼676.4(8) A ,
Z¼3, m¼0.425 mmꢁ1; 1913 independent reflections (Rint¼
0.0484), R indices (all data) R1¼0.0894, wR2¼0.1282.
Compound 9: C14H9ClO7, M 324.66, monoclinic space
˚
˚
3.5.2. 6-Chloro-5,8-dihydroxy-2-methoxynaphtho-1,4-
group
C2/c,
˚
a¼16.0510(8) A,
b¼5.5590(8) A,
c¼
quinone (11, R¼Me, R0¼H)
30.980(8) A, V¼27,437(9) A , Z¼8, m¼0.313 mmꢁ1, 1826 in-
dependent reflections (Rint 0.0742), R indices (all data) R1
0.1202, wR2¼0.2532.
3
˚
6-Chloro-2,5,8-trihydroxynaphtho-1,4-quinone
(1.36 g,
5.0 mmol) in BF3$MeOH complex (10 cm3) was refluxed for
2 h, allowed to cool and then poured into water (100 cm3).
The mixture was carefully treated with sodium carbonate solu-
tion until gas evolution ceased, and the suspended solid was fil-
tered, washed and air dried to give a red-black product (0.98 g,
89%), mp 182e186 ꢀC. dH (80 MHz, CDCl3) 3.95 (3H, s, 2-
Me), 6.19 (1H, s, 3-H), 7.35 (1H, s, 7-H), 12.15 (2H, 2s, 5-
OH, 8-OH, exch. D2O); m/z 256 (Mþ, 5%), 254 (Mþꢁ2, 100%).
Compound 12a: C21H16O10, M 428.34, triclinic, space
˚
˚
˚
group PI, a¼8.295(4) A, b¼8.8970(10) A, c¼12.799(8) A,
V¼922.0(7) A , Z¼2, m¼0.125 mmꢁ1, 2459 independent
3
˚
reflections (Rint 0.0518), R indices, all data: R1¼0.0836,
wR2¼0.1125.
Acknowledgements
3.5.3. iso-Propyl 6-methoxy-3,4,8-trihydroxy-1-methyl-
anthra-9,10-quinone-2-carboxylate (12b, R¼Me, R1¼H,
R2¼iPr)
Financial support is acknowledged from the SPUR initia-
tive (DTI) accessed by Mr. M. Armitage of European Colour.
We thank Prof. S.M. Roberts (Exeter University) and Prof. M.
Hursthouse (University of Wales, Cardiff) for facilitating and
effecting X-ray structural determinations. Discussion and crit-
ical comments from late Mr. G. Marshall (European Colour)
are also greatly appreciated.
A stirred solution of 6-chloro-5,8-dihydroxy-2-methoxy-
naphtho-1,4-quinone (25 mg, 0.010 mmol) with (E)- and (Z)-
3-isopropoxycarbonyl-2,4-bis(trimethylsilyloxy)penta-1,3-dienes
8b (66 mg, 0.02 mmol) in dry toluene (5 cm3) was refluxed
for 48 h. The mixture was then evaporated to dryness and pu-
rified by column chromatography on silica gel (chloroform) to
afford an orange solid (16 mg, 42%), which crystallised (tolu-
ene) as orange needles, mp 246e249 ꢀC. dH (80 MHz, CDCl3)
1.46 (6H, d, (CH3)2CHOCO, J 6 Hz), 3.00 (3H, s, 1-Me), 3.99
(3H, s, 6-OMe), 5.41 (1H, sept. OCOCH(CH3)2 J 6 Hz), 6.72
(1H, s, 7-H), 7.83 (1H, s, 4-H), 10.31 (1H, s, 3-OH, exch.
D2O), 13.18, 13.82 (2H, 2s, 5-OH, 8-OH, exch. D2O); m/z
387 (MþþH, 11), 386 (Mþ, 51%), 344 (19), 343 (20), 328
(11), 327 (60), 326 (100), 298 (14), 58 (14), 43 (40), 18 (10).
References and notes
1. Thomson, R. H. Naturally-Occurring Quinones; Academic: New York,
NY, 1971; pp 458e459.
2. Allevi, P.; Anastasia, M.; Bingham, S. J.; Ciuffreda, P.; Fiecchi, A.;
Cighetti, G.; Muir, M.; Scala, A.; Tyman, J. H. P. J. Chem. Soc., Perkin
Trans. 1 1998, 575; Tyman, J. H. P. Synthetic and Natural Phenols;
Elsevier: Amsterdam, 1996; pp 626e632.
3. Bingham, S. J.; Tyman, J. H. P. Chem. Commun. 2000, 925; Tyman, J. H.
P.; Bingham, S. J. British Patent 2358016, 2000; Chem. Abstr. 2001, 133,
135152.
4. Bingham, S. J.; Tyman, J. H. P. J. Chem. Soc., Perkin Trans. 1 1997, 3637;
Venkataraman, K.; Rama Rao, A. V. Some Recent Developments in the
Chemistry of Natural Products; Prentice Hall of India: New Delhi, 1972.
5. Verhecken, A. J. Soc. Dyers Col. 1989, 105, 389.
3.5.4. 6-Chloro-2,5,8-trihydroxy-3-(1-methyl-2-ethoxy-
carbonyl-3-oxobutyl)naphtho-1,4-quinone (13)
To a stirred solution of 6-chloro-2,5,8-trihydroxynaphtho-
1,4-quinone (0.050 g, 0.180 mmol) and (E)- and (Z)-3-ethoxy-
carbonyl-3-penten-2-ones (0.050 g, 0.320 mmol) in DMF
(5 cm3) at ambient temperature, piperidine (1 drop) was
added. After 24 h, the mixture was acidified with 0.5 M hydro-
chloric acid (50 cm3) and extracted with dichloromethane, and
the extracts were dried (magnesium sulfate), filtered and con-
centrated to give a red solid, which was purified by column
chromatography (SiO2, chloroform) to give a dark red solid
(0.067 g, 94%), which crystallised (ethanol) as dark red
prisms, mp 134e141 ꢀC. dH (80 MHz, CDCl3), 1.28 (3H, d,
1-CH3, J 7 Hz), 1.32 (3H, t, CH3CH2OCO, J 7 Hz), 2.18 (3H,
6. Roberge, G.; Brassard, P. J. Chem. Soc., Perkin Trans. 1 1978, 1041.
7. Cameron, D. W.; Deutscher, D. J.; Feutrill, G. I.; Griffiths, P. G. Aust. J.
Chem. 1981, 34, 2401.
8. Chang, C. T.; Young, M. F.; Chen, F. C. Formosan Sci. 1962, 16, 29.
9. Sartori, G.; Bigi, F.; Canali, G.; Maggi, R.; Casnati, G.; Tao, X. J. Org.
Chem. 1993, 58, 840.
10. The 2-, 5- and 8-OH groups in 3 (form 1) are hydrogen-bonded as seen in
the 1H NMR spectrum with d (DMSO-d6) at 12.75 (br s), 11.70, 13.35 ppm,
respectively, cf. (CDCl3) (Sadtler 19857), 10.34 for lawsone (2-hydroxy-
naphtho-1,4-quinone and d Me2CO (Sadtler 3230), 8.35 for 2-naphthol.
No NMR data for the 2-OH are given in Ref. 9 by Farina, F.; Martinez-
Utrilla, R.; Parades, M. C. Synthesis 1981, 300 , who do not list the 2-
OH group in data for 2-hydroxy-5,8-dimethoxynaphth-1,4-quinone.