An improved synthetic procedure for 6,6′-dibromoindigo (Tyrian purple)

Article abstract of DOI:10.1081/SCC-100107023

Tyrian purple was the most precious dye of antiquity. We describe a simple synthetic procedure that yields the actual dye, 6,6′-dibromoindigo 1, in considerably improved overall yield and of analytical purity, also being amenable to scale-up.

Full text of DOI:10.1081/SCC-100107023

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AN IMPROVED SYNTHETIC PROCEDURE FOR 6,6′-
DIBROMOINDIGO (TYRIAN PURPLE)
Peter Imming a , Ingo Imhof a & Matthias Zentgraf a
a Institut für Pharmazeutische Chemie, Philipps-Universität, Marburg, 35032, Germany
Published online: 16 Aug 2006.
To cite this article: Peter Imming , Ingo Imhof & Matthias Zentgraf (2001): AN IMPROVED SYNTHETIC PROCEDURE FOR
6,6′-DIBROMOINDIGO (TYRIAN PURPLE), Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:23, 3721-3727
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SYNTHETIC COMMUNICATIONS, 31(23), 3721–3727 (2001)
AN IMPROVED SYNTHETIC
PROCEDURE FOR
6,60-DIBROMOINDIGO
(TYRIAN PURPLE)
Peter Imming,* Ingo Imhof,
and Matthias Zentgraf
Institut fur Pharmazeutische Chemie,
Philipps-Universitat, 35032 Marburg,
Germany
ABSTRACT
Tyrian purple was the most precious dye of antiquity. We
describe a simple synthetic procedure that yields the actual
dye, 6,60-dibromoindigo 1, in considerably improved overall
yield and of analytical purity, also being amenable to scale-up.
INTRODUCTION
Tyrian purple was the most valuable dye in ancient history.1 Kings
and emperors wore it to display their power and wealth.2 The Roman
emperor Nero made the right of wearing purple a prerogative to himself
and his family.3 In antiquity, purple was produced by extraction of the
* Corresponding author. E-mail: imming@mailer.uni-marburg.de
3721
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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IMMING, IMHOF, AND ZENTGRAF
secretions of a gland of Mediterranean gastropod molluscs (Murex bran-
daris, Murex trunculus, Purpura haemastoma, and others).4
The fact that 12,000 purple snails are necessary to get just 1.4 g of
pure dye5 illustrates how expensive and valuable purple was (and is).
Friedlaender showed in 19095 that purple is the 6,60-dibromo derivative 1
of indigo 2 (Figure 1). Its structure was finally proven by two independent
X-ray analyses.6 The colourless secretion extracted from snails contains
the precursors of the actual dye. It consists of sulfate esters of substituted
indoxyls and of indoxyl itself (3). They are accompanied by a purpurase
which catalyzes their hydrolysis, followed by light-assisted air oxidation to
6,60-dibromoindigo (6,60-dibromoindigotin) 1.7
The dye is still needed today, for the purpose of restoration and analy-
sis of ancient cloths, paintings etc, and for the production of exclusive pieces
of garment.8 Chemical synthesis will have the preference over production
from molluscs as the former will be less cumbersome and make larger
amounts available. The recent surge of interest in indigo derivatives
in medicinal chemistry also prompts us to disclose the details of our
synthetic procedure. Indirubin 4 was shown to be a good and selective
inhibitor of cyclin-dependent kinases that are a very promising new
target for anti-tumor therapy; so derivatives and isomers of 4 are
being sought for.9 Tryptanthrin 5, an alkaloid from plants yielding indigo,
is the first natural compound to inhibit cyclooxygenase-2 more than
Figure 1. Indigoids.

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3723
cyclooxygenase-1, a new therapeutic concept excepted to reduce the side-
effects of antirheumatic drug therapy.10
As direct bromination of indigo leads to 5,50-, 7,70- and 4,40-dibromo-
indigo derivatives,11 any synthesis must incorporate the bromine in the
desired position prior to the construction of the indigo skeleton.
A few synthetic routes to 6,60-dibromoindigo were published.
They require the preparation of 4-bromo-2-nitrobenzaldehyde 10 as
the direct precursor of the dye. A synthesis published by Friedlaender
has only historical interest.12 Voß et al. published a synthesis of 10 by an
organometallic methodology13 which poses difficulties if one wants to
prepare large amounts of dibromoindigo. In view of the unsatisfactory
situation concerning the preparation of 1, another route was published
recently, proceeding via a nitrone and requiring five steps, some of them
fairly tedious.14
RESULTS
We undertook to modify a five-step synthetic scheme which starts
with 4-methylaniline 6 (Figure 2).15 Our objectives were, firstly, to increase
the fairly low yields of some steps and optimize the whole sequence;
Figure 2. Preparation of 6,60-dibromoindigo.

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IMMING, IMHOF, AND ZENTGRAF
secondly, to get dibromoindigo of analytical purity; thirdly, to obtain
pure dibromoindigo instead of the mixture of bromo- and chloroindigos
one gets via the published procedure. The latter fact – that they obtained
a mixture – seems to have elapsed the attention of the authors since they
state to have prepared pure 6,600dibromoindigo. This is probably due to the
fact that the colours of 6,60-dichloro- and 6,60-dibromoindigo are very simi-
lar16 and NMR spectra difficult to record because of the very low solubility
of 1. The mass spectra of indigoids, however, are dominated by a very
strong molecule ion, the type and number of halogens being easily deducible
from the isotope pattern.
For each step, we explored various reaction conditions, also trying
to simplify the procedure to make it amenable to scale-up. In the experi-
mental part, details of the optimal procedure and conditions are summar-
ized, so they will not be repeated here. For the final step, preparation of
the actual dye, a somewhat more circuitous procedure was published,17
but in our hands did not give better yields than the simpler one we selected.
We thus obtained pure 6,60-dibromoindigo from commercially available
4-methylphenylamine 6 in five steps with an overall yield of 10%, a
substantial improvement compared to the literature (2.8%15b and 5.4%15a).
EXPERIMENTAL
3-Nitro-4-methylphenylammonium Hydrogensulfate (7): 4-Methylphe-
nylamine (270 g, 2.5 mol) was cautiously dissolved in sulphuric acid (96%,
1350 g) with stirring and cooled to À5ꢀC with an ice/salt bath. A mixture of
sulphuric acid (96%, 900 g) and concentrated nitric acid (252 g, 2.6 mol)
was added dropwise with stirring over a period of a few hours, maintaining
the temperature at À5ꢀC to avoid dinitration. The resulting brown mixture
was kept overnight at this temperature and poured over crushed ice (4 kg).
A dark yellow solid separated. It was filtered off, washed with ice water and
dried, yielding 407 g (1.6 mol, 64%) of yellow crystals. IR (KBr): 3400, 2948,
2553, 1642, 1536 cmÀ1
.
1H NMR (500 MHz, CDCl3): d ¼ 7.22 (d, 1H,
J ¼ 2.52 Hz, 2-H), 7.02 (d, 1H, J ¼ 8.71 Hz, 5-H), 6.74 (dd, 1H, J ¼ 2.75
and 8.02 Hz, 6-H), 2.40 (s, 3H, CH3). The constitution was further proved
by conversion to 3-nitro-4-methylphenylamine: IR (KBr): 3387, 2931, 1627,
1520, 1349 cmÀ1. 1H NMR (500 MHz, CDCl3): d ¼ 7.22 (d, 1H, J ¼ 2.52 Hz,
2-H), 7.02 (d, 1H, J ¼ 8.25 Hz, 5-H), 6.74 (dd, 1H, J ¼ 2.52 and 8.25 Hz,
6-H), 3.75 (NH2), 2.40 (s, 3H, CH3). MS (70 eV) m/z (%): 152 (Mþ, 90),
77 (100). Anal. calc. for C7H8N2O2 (152.17): C, 55.31; H, 5.31; N, 18.43;
found: C, 54.80; H, 5.38; N, 17.59.

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3725
4-Bromo-2-nitromethylbenzene (8): 3-Nitro-4-methyphenylammonium
hydrogensulfate (358 g, 1.4 mol) was suspended in a mixture of water (1.5 L)
and hydrobromic acid (48%, 450 mL) and cooled to 0ꢀC with an ice/salt
bath. An ice-cold solution of sodium nitrite (180 g, 2.6 mol) in water
(450 mL) was slowly added to the stirred suspension, keeping the tempera-
ture at 0ꢀC. The reaction was completed when starch–iodide paper indicated
the presence of nitrous acid in the mixture. In a 6-L three-necked flask a
solution of copper(I) bromide (202.5 g, 1.4 mol) in hydrobromic acid (48%,
270 mL) was prepared and heated to reflux. Portions of the ice-cold solution
of the diazonium salt were added. Brown gases escaped from the solution
and a viscous liquid was generated. Progress of the reaction was monitored
by tlc. The resulting viscous liquid was extracted with tert-butyl methyl
ether. The combined organic layers were washed twice with ammonia
(5%) and water, dried over magnesium sulfate and filtered. Evaporation
left a brown oil from which a brownish yellow solid separated.
Recrystallisation from ethanol yielded 176 g (58%) of a dark yellow solid,
m.p. 45ꢀC. IR (KBr): 2993, 1529, 1338 cmÀ1. H NMR (500 MHz, CDCl3):
1
d ¼ 8.04 (d, 1H, J ¼ 2.1 Hz, 3-H), 7.54 (dd, 1H, J ¼ 1.8 and 8.3 Hz, 5-H), 7.16
(dd, 1H, J ¼ 0.5 and 8.3 Hz, 6-H), 2.48 (d, 3H, J ¼ 0.5 Hz, CH3). MS (70 eV)
m/z (%) ¼ 215/217 (Mþ, 27), 90 (100). Anal. calc. for C7H6BrNO2 (216.07):
C, 38.92; H, 2.80; N, 6.48; Br, 36.88; found: C, 38.99; H, 2.92; N, 6.52;
Br, 38.32.
4-Bromo-2-nitrobenzylidene Diethanoate (9): 4-Bromo-2-nitromethyl-
benzene (130 g, 0.6 mol) was suspended in a mixture of glacial acetic acid
(260 mL) and acetic anhydride (1450 mL) with stirring. Sulphuric acid (96%,
140 mL) was carefully added, and the resulting solution cooled to 5ꢀC.
A solution of chromium(VI) oxide (165 g, 1.65 mol) in water (100 mL)
and glacial acetic acid (663 mL) was added dropwise over a period of 8 h,
keeping the temperature between 5 and 10ꢀC. The resulting dark green
viscous liquid was stirred for another hour and poured into 2–3 kg ice
water. A white solid separated, which was removed by filtration, washed
and dried, yielding 130 g (65%) of m.p. 132ꢀC. IR (KBr): 3112, 2940, 1748,
1
1529, 1363 cmÀ1. H NMR (500 MHz, CDCl3): d ¼ 8.19 (d, 1H, J ¼ 2.2 Hz,
3-H), 8.12 (s, 1H, a-CH), 7.82 (dd, 1H, J ¼ 2.0 and 8.5 Hz, 5-H), 7.60 (d, 1H,
J ¼ 8.5 Hz, 6-H), 2.14 (s, 6H, CH3). MS (70 eV) m/z (%) ¼ 331/333 (Mþ, 6),
43 (100). Anal. calc. for C11H10BrNO6 (332.10): C, 39.78; H, 3.03; N, 4.22;
Br, 24.05; found: C, 39.86; H, 3.24; N, 4.41; Br, 25.06.
4-Bromo-2-nitrobenzaldehyde (10): 4-Bromo-2-nitrobenzylidene diet-
hanoate (93 g, 0.28 mol) was heated to reflux in a mixture of ethanol
(645 mL) and 1 M sulphuric acid (645 mL) for 1.5 h. After cooling to
room temperature, the colourless, slightly turbid solution was poured into
1 L of cold water, precipitating the aldehyde as a faintly yellow solid. It was

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IMMING, IMHOF, AND ZENTGRAF
filtered off, washed with ice water and dried over silica gel, yielding 60 g
(93%), m.p. 95ꢀC. IR (KBr) 3093, 2919, 1686 cmÀ1. H NMR (500 MHz,
1
CDCl3): d ¼ 10.39 (s, 1H, CHO), 8.27 (d, 1H, J ¼ 1.8 Hz, 3-H ), 7.93 (ddd,
1H, J ¼ 1.1, 4.5 and 7.6 Hz, 5-H), 7.85 (d, 1H, J ¼ 8.2 Hz, 6-H). MS (70 eV)
m/z (%) 229/231 (Mþ, 8), 199/201 (100). Anal. calc. for C7H4BrNO3
(230.01): C, 36.55, H, 1.75; Br, 34.74; N, 6.09; found: C, 36.88; H,
2.01; Br, 34.90; N, 603.
6,60-Dibromoindigo (Tyrian Purple) (1): 4-Bromo-2-nitrobenzaldehyde
(50 g, 0.22 mol) was dissolved in acetone (2250 mL). 2500 mL of water were
added in small amounts. On dropwise addition of 2 N aqueous sodium
hydroxide solution, maintaining the pH at 10, the product gradually
formed and precipitated. The suspension was stirred overnight. The preci-
pitate was filtered off, washed with acetone and water and evaporated to
dryness, yielding 20 g (44%) of 6,60-dibromoindigo, m.p. >300ꢀC. IR
(KBr): n ¼ 3384, 1610, 1580, 1438, 1314, 1157 cmÀ1. MS (70 eV) m/z (%)
418/420/422 (Mþ, 100). Anal. calc. for C16H8Br2N2O2 (420.06): C, 45.75;
H, 1.92; N, 6.70; Br, 38.04; found: C, 45.60; H, 2.10; N, 6.50; Br, 37.80.
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3. C. Suetonius Tranquillus, Vita Neronis, 32, 3.
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Received in the USA February 9, 2001

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