Studies directed toward total synthesis of rhodocomatulins: A regioselective synthesis of brominated hydroxyanthraquinones by anionic annulations

Article abstract of DOI:10.1080/00397911.2017.1401637

In this work, brominated hydroxyanthraquinones, which are the core structural motif of naturally occurring bromorhodocomatulins, were successfully synthesized using Hauser annulation reaction as the key step. When brominated Michael acceptors (brominated p-quinone monoketals) and cyanophthalides or bromocyanophthalides (Hauser donors) were reacted under the annulation conditions, brominated anthraquinones were obtained with 81–87% yields for four examples. On acidic quenching, products were obtained as solid which were separated by filtration and purified by recrystallization in acetone. No chromatography was required.

Full text of DOI:10.1080/00397911.2017.1401637

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Studies directed toward total synthesis of
rhodocomatulins: A regioselective synthesis of
brominated hydroxyanthraquinones by anionic
annulations
Md Raja Sk, Soumen Chakraborty & Dipakranjan Mal
To cite this article: Md Raja Sk, Soumen Chakraborty & Dipakranjan Mal (2018):
Studies directed toward total synthesis of rhodocomatulins: A regioselective synthesis of
brominated hydroxyanthraquinones by anionic annulations, Synthetic Communications, DOI:
10.1080/00397911.2017.1401637
To link to this article: https://doi.org/10.1080/00397911.2017.1401637
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Date: 10 January 2018, At: 04:14

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1401637
Studies directed toward total synthesis of rhodocomatulins:
A regioselective synthesis of brominated
hydroxyanthraquinones by anionic annulations
Md Raja Sk, Soumen Chakraborty, and Dipakranjan Mal
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, India
ABSTRACT
ARTICLE HISTORY
In this work, brominated hydroxyanthraquinones, which are the core
structural motif of naturally occurring bromorhodocomatulins, were
successfully synthesized using Hauser annulation reaction as the key
step. When brominated Michael acceptors (brominated p-quinone
monoketals) and cyanophthalides or bromocyanophthalides (Hauser
donors) were reacted under the annulation conditions, brominated
anthraquinones were obtained with 81–87% yields for four examples.
On acidic quenching, products were obtained as solid which were
separated by filtration and purified by recrystallization in acetone. No
chromatography was required.
Received 23 August 2017
KEYWORDS
Brominated
hydroxyanthraquinones;
Hauser annulation;
rhodocomatulins
GRAPHICAL ABSTRACT
Introduction
Anthraquinones are the largest group of naturally occurring quinones that are based on
,10-anthraquinone skeleton, and have been isolated from higher plants, bacteria, lichens,
9
[
1]
and fungi. They embody anticancer drugs, dyes, chemical sensors, organogelators, liquid
[
2]
crystals, and so on. The cytotoxicity of anthraquinones arise due to their binding
with DNA reversibly by intercalation and generation of hydroxyl radical which breaks
DNA strands. Their planarity allows an intercalation between the DNA base pairs and
significantly affected by the different substituents at the planar ring system of
[
3–5]
anthraquinones.
Like other classes of halogenated compounds halogenated anthraquinones are also
found in nature especially, as marine natural products. Recently, Khokhar et al. have
reported three new halogenated anthraquinone metabolites 3-bromo-6-methoxy-12-
desethylrhodocomatulin 7-methyl ether (1), 3-bromo-6-methoxyrhodocomatulin 7-methyl
CONTACT Dipakranjan Mal
dmal@chem.iitkgp.ernet.in
Department of Chemistry, Indian Institute of Technology
Kharagpur, Kharagpur 721302, India.
1
13
Supplemental data (full experimental detail, H and C NMR spectra) can be accessed on the publisher’s website.
2017 Taylor & Francis
©

2
M. R. SK ET AL.
Figure 1. Naturally occurring halogenated anthraquinones.
ether (2), and 3-bromorhodocomatulin 7-methyl ether (3) from the Australian marine
[
6]
invertebrate Clathria hirsuta (Australian sponge from the Great Barrier Reef). Com-
[
7]
pounds 4–11 were derived from Aspergillus sp. SCSIO F063 and cytotoxic compound
2, a bromoderivative of emodic acid and dimeric halogenated anthraquinones gymno-
chromes E (13), gymnochromes F (14), and isogymnochrome B (15) were isolated from
1
[
8]
deep-water crinoids, Holopus rangii. Again brominated anthraquinone pigments proiso-
[
9]
crinins A–F (16–22) were isolated from the stalked crinoid Proisocrinus ruberrimus
Fig. 1).
For the synthesis of halogenated anthraquinones similar to brominated rhodocomatu-
lins, we proposed that the key step for the formation of B ring of the anthraquinone
(
[
10]
(
23) could be Hauser annulation
of a phthalide, a Michael donor (24) with a para-
quinonemonoketal, a Michael acceptor (25). Thus, it is expected that the retrosynthetic
pathway for the total synthesis of naturally occurring compounds 1–3 would depends
[
11]
on photoxidation
followed by Hauser annulation (Scheme 1).
Results and discussion
With this strategy in mind, we focused on simple brominated anthraquinones as
key intermediates. Although the brominated hydroxyanthraquinones can be accessed by

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Scheme 1. Retrosynthetic analysis of naturally occurring halogenated anthraquinones.
late-stage of bromination of the corresponding hydroxyanthraquinones, regioselectivity
becomes a major problem. To solve the regioselective issue, which is exhaustively studied
in benzene derivatives, p-cresol (26) was brominated selectively at C-2 position to give
2
-bromo-4-methyl phenol (27) using very cheap source of bromine, i.e., aqueous HBr
[
12]
(
47%) and DMSO (1:1) as disclosed by Song et al.
The compound 27 on oxidative
dearomatization with PhI(OAc) (PIDA) in MeOH under nitrogen atmosphere yielded
2
[
13]
2
-bromo-4-methoxy-4-methyl-2,5-cyclohexadien-1-one (28) (Scheme 2).
A similar type Michael acceptor, i.e., 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one (30)
[
14]
was synthesized from 4-bromophenol (29) according to the procedure of Matveeva et al.
(Scheme 3).
Phthalides (Hauser donors) were prepared by the literature reported procedures.[15]
-Cyanophthalide, i.e., 1,3-dihydro-3-oxo-1-sobenzofurancarbonitrile (32) was prepared
3
from 3-hydroxy-2-benzofuran-1(3H)-one (31) by treating with KCN and HCl at 0 °C
and then with oxalyl chloride in DMF at − 78 °C and finally with pyridine (Scheme 4).
Another 3-cyanophthalide, i.e., 6-bromo-1,3-dihydro-3-oxo-1-isobenzofurancarboni-
trile (36) was synthesized from commercially available 5-bromophthalide (33). First, C-3
position of 33 was monobrominated using 1 equiv. of bromine in CCl to obtain a mixture
4
of compounds containing 34 and the resultant mixture was subjected to hydrolysis to give
4
-bromo-2-formyl-benzoic acid (35). It was then converted to cyanophthalide 36 through
cyanohydrin intermediate with an overall yield 32% for four steps (Scheme 5).
Scheme 2. Synthesis of halogenated p-quinonemonoketal 28.
Scheme 3. Synthesis of quinone acceptor 30.

4
M. R. SK ET AL.
[
15]
Scheme 4. Synthesis of cyanophthalide 32.
Scheme 5. Synthesis of 5-bromo-3-cyanophthalide (36).
Two more cyanophthalides, 1,3-dihydro-4,5-dimethoxy-3-oxo-1-isobenzofurancarboni-
trile (37) and 1,3-dihydro-4-methoxy-6-methyl-3-oxo-1-Isobenzofurancarbonitrile (38)
were synthesized according to the literature procedures[16,17] (Fig. 2).
[
18,19]
Very little work has been reported on the synthesis of halogenated anthraquinones.
Conventionally, they are prepared by halogenation[20–22] of the corresponding anthraqui-
nones. Herein, halogenated Hauser donors and/or halogenated Michael acceptors were
treated with lithium tert-butoxide under Hauser annulation conditions. Thus, the reaction
between Hauser donor 32 and p-quinonemonoketal 28 yielded 2-bromo-1-hydroxy-4-
methyl-9,10-anthracenedione (39) in 85% yield after recrystallization from acetone. The
[
23]
compound 39 constitutes an ingredient for a fungicidal composition.
Similarly, other
donors 36 and 37 on reaction with the acceptor 28 yielded 2,6-dibromo-1-hydroxy-4-
methyl-9,10-anthracenedione (40) in 87% yield and 2-bromo-1-hydroxy-7,8-dimethoxy-
4
-methyl-9,10-anthracenedione (41) in 84% yield respectively after recrystallization from
acetone. 2-Bromo-1-hydroxy-8-methoxy-4,6-dimethyl-9,10-anthracenedione (42) was
t
obtained in 81% yield from donor 38 with its tautomeric form 42 under the same reaction
1
3
conditions. C NMR data indicated two carbonyl carbon in each case between δ 180 and
1
13
1
90 ppm and other data from H NMR, C NMR, and DEPT-135 leave no ambiguity on
[
16,24]
the formation of the annulated products and the formation of the anthraquinones.
Interestingly, Hauser annulation took place selectively at 5,6-double bond of the anthraqui-
none rather than at 2,3-double bond of the same and in each case, bromine was retained in
the annulated product. The merits of the reaction lie in its regioselectivity and easy
Figure 2. 3-Cyanophthalides 37 and 38.

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Scheme 6. General Scheme for the synthesis of halogenated anthraquinones by Hauser annulation.
purification of the products. In each case, after quenching the reaction with saturated
NH Cl solution, the products separated as solids, which were filtered and purified only
4
by recrystallization from acetone. Scheme 6 and Table 1 illustrate the synthesis of haloge-
nated anthraquinones from corresponding phthalides (A) and p-quinonemonoketals (B).
The mechanism for the formation of the brominated hydroxyanthraquinones 39-42 can
[
10]
be similar as the one reported by Mal et al. (Scheme 7). Cyclohexadienone 28 undergoes
Michael addition with carbanion 44, formed by deprotonation of active hydrogen of A to
a
Table 1. Annulation for the synthesis of halogenated hydroxyanthraquinones yield after
recrystallization.
Entry
a
Hauser donor
Acceptor
Bromoanthraquinone
Yield (%)
85
1
2
3
87
84
4
5
81
36

6
M. R. SK ET AL.
Scheme 7. Mechanism of formation of halogenated anthraquinones by Hauser annulation.
form enolate (45). 45 then undergoes intramolecular ring closure to form a tetracyclic
−
intermediate 46, which on elimination of CN formed a triketo intermediate 47. On
t
acidification, intermediate 47 loses methanol and tautomerizes to form C or C .
Though the existence of the tautomeric forms for 1-hydroxy-9,10-anthraquinones is
[
25]
t
quite known,
a significant amount of the tautomer, 42 was observed and it was con-
1
t
firmed from HNMR spectrum that the ratio of 42 and 42 was 2:1 and they could not be
isolated by column chromatography (Scheme 8).
For entry 5, Table 1 the acceptor 30, i.e., 2,4,4,6-tetrabromo-2,5-cyclohexadienone is
[
26]
t
−
well known to provide electrophilic bromine.
Therefore, the attack of BuO at C4 bro-
mine, which is electrophilic in nature, takes place to produce tribromophenol (Scheme 9).
Scheme 8. Tautomer of 42.
Scheme 9. Plausible mechanism for the formation of 43.

SYNTHETIC COMMUNICATIONS®
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Conclusion
In conclusion, brominated hydroxyanthraquinones have successfully been synthesized with
high regioselectivity using Hauser annulation with yields 81–87%. Use of DMSO-HBr as
brominating agent for aromatic ring for the synthesis of p-quinonemonoketals, use of
lithium tert-butoxide as base in Hauser annulation instead of using LDA and easy separ-
ation of halogenated anthraquinones by filtration and recrystallization minimize the overall
cost for the synthesis of halogenated anthraquinones indicating a path for the cost-effective
and regioselective total synthesis of the brominated Rhodocoumatulins. The applications to
assemble the corresponding iodoanthraquinones are being studied.
Experimental
General procedure for Hauser annulation
To a stirred solution of lithium tert-butoxide (LTB, 3 equiv.) in THF at − 78 °C (EtOAc/liq.
N bath) under an inert atmosphere was added a solution of phthalide (1 equiv.) in THF.
2
The resulting solution was stirred for 30 min followed by addition of Michael acceptor
(
1.2 equiv.) in THF and keeping the mixture at the same temperature for 1 h. The reaction
mixture was then stirred for 5 h at room temperature (25 °C) and quenched with 10%
NH Cl solution. The bright yellow solid precipitated was filtered and washed with
4
petroleum ether. It was then dissolved in acetone by gentle heating and purified by
recrystallization.
2-Bromo-1-hydroxy-4-methyl-9,10-anthracenedione (39)
This was prepared from cyanophthalide 32 and acceptor 28 in 85% yield following the
general procedure described above for the Hauser annulation. Yellow solid, mp: 240 °C
−
1
(
decomp.). R ¼ 0.57 (1:10 EtOAc: pet ether); FTIR (cm ) 3400, 2928, 1660, 1632, 1586,
f
1
1
439, 1406, 1353, 1282, 1249, 1224, 1081, 789, 720, 591, 540; H NMR (400 MHz, CDCl )
3
13
δ (ppm) 13.88 (s, 1H), 8.30–8.25 (m, 2H), 7.82 (d, J ¼ 9.2 Hz, 3H), 2.73 (s, 3H);
C
NMR (150 MHz, CDCl ) δ (ppm) 189.10, 184.0, 158.43, 144.16 (CH), 135.09 (CH),
3
1
2
34.91, 134.49, 133.83 (CH), 132.03, 129.33, 127.41 (CH), 126.72 (CH), 118.63, 117.0,
2.90 (CH ); Anal. Calcd. for C H BrO : C, 56.81; H, 2.86; found: C, 56.69; H, 2.49%.
3
15
9
3
2
,6-Dibromo-1-hydroxy-4-methyl-9,10-anthracenedione (40)
This was prepared from cyanophthalide 36 and acceptor 28 in 87% yield following the
general procedure described above for the Hauser annulation. Yellow solid, mp: 222 °C
−
1
(
decomp.). R ¼ 0.63 (1:10 EtOAc: pet ether); FTIR (cm ) 3430, 2926, 1662, 1631, 1577,
f
1
1
438, 1397, 1351, 1259, 1215, 1160, 1078, 812, 784, 754, 573, 510; H NMR (600 MHz,
CDCl ) δ (ppm) 13.78 (s, 1H), 8.39 (s, 1H), 8.16 (d, J ¼ 7.5 Hz, 1H), 7.93 (d, J ¼ 7.5 Hz,
3
1
3
1
1
1
2
H), 7.84 (s, 1H), 2.73 (s, 3H); C NMR (150 MHz, CDCl ) δ (ppm) 188.26, 182.44,
3
58.54, 144.37 (CH), 136.93 (CH), 135.42, 135.28, 130.92, 130.64, 130.53 (CH), 128.92,
28.42 (CH), 119.17, 116.75, 22.88 (CH ); Anal. Calcd. for C H Br O : C, 45.49; H,
3
15
8
2 3
.04; found: C, 45.57; H, 2.31%.
2
-Bromo-1-hydroxy-7,8-dimethoxy-4-methyl-9,10-anthracenedione (41)
This was prepared from cyanophthalide 37 and acceptor 28 in 84% yield following the
general procedure described above for the Hauser annulation. Yellow solid, mp:>250 °C

8
M. R. SK ET AL.
−
1
(
decomp.). R ¼ 0.59 (1:3 EtOAc: pet ether); FTIR (cm ) 3430, 2947, 2365, 1635, 1573,
f
1
1
438, 1403, 1348, 1334, 1286, 1249, 1225, 1074, 1031, 810, 460; H NMR (600 MHz, CDCl )
3
δ (ppm) 14.02 (s, 1H), 8.12 (d, J ¼ 8.4 Hz, 1H), 7.79 (s, 1H), 7.33 (d, J ¼ 8.4, 1H), 4.02 (d,
1
3
J ¼ 10.8, 6H), 2.72 (s, 1H); C NMR (150 MHz, CDCl ) δ (ppm) 189.11, 183.10, 158.67,
3
1
1
5
58.20, 149.80, 143.55 (CH), 133.93, 129.20, 128.09, 125.31, 125.26 (CH), 118.38, 118.25,
17.22 (CH), 61.37 (CH ), 56.38 (CH ), 22.79 (CH ). Anal. Calcd. for C H BrO : C,
3
3
3
17 13
5
4.13; H, 3.47; found: C, 54.43; H, 3.12%.
2
-Bromo-1-hydroxy-8-methoxy-4,6-dimethyl-9,10-anthracenedione (42)
This was prepared (along with its tautomer) from cyanophthalide 38 and acceptor 28 in
8
1% yield following the general procedure described above for the Hauser annulation.
−1
Yellow solid, mp: 228 °C (decomp.). R ¼ 0.67 (1:5 EtOAc: pet ether); FTIR (cm )
f
1
3
432, 2930, 2365, 1600, 1401, 1347, 1319, 1304, 1234, 1215, 1116, 800, 468. For 42: H
NMR (600 MHz, CDCl ) δ (ppm) 14.26 (s, 1H), 7.75 (s, 1H), 7.64–7.63 (m, 1H), 7.05
3
13
(s, 1H), 3.98 (s, 3H), 2.82 (s, 3H), 2.70 (s, 3H); C NMR (150 MHz, CDCl ) δ (ppm)
3
1
1
89.93, 184.26, 163.71, 158.09, 145.29, 142.80 (CH), 138.42, 133.89, 129.11, 124.13 (CH),
23.54, 118.89, 117.87, 109.49 (CH), 55.83 (CH ), 24.06 (CH ), 22.73 (CH ).
3
3
3
t
1
For 42 : H NMR (600 MHz, CDCl ) δ (ppm) 13.4 (s, 1H), 7.64–7.63 (m, 1H), 7.55
3
13
(s, 1H), 7.08 (s, 1H), 3.99 (s, 3H), 2.92 (s, 3H), 2.82 (s, 3H); C NMR (150 MHz, CDCl )
3
δ (ppm) 189.55, 183.94, 164.02, 160.33, 145.51, 138.35, 134.85, 131.38, 128.25 (CH), 124.35
CH), 121.84, 120.31, 116.60, 109.85 (CH), 55.92 (CH ), 23.92 (CH ), 20.18 (CH ). Anal.
(
3
3
3
Calcd. for C H BrO : C, 56.53; H, 3.63; found: C, 56.34; H, 3.41%.
1
7
13
4
Funding
We gratefully acknowledge the Council of Scientific and Industrial Research (CSIR) for financial
support (02(0183)/14/EMRII), and The Department of Science and Technology (DST) for instru-
mental facilities. Md Raja Sk is thankful to IIT Kharagpur and Soumen Chakraborty is thankful
to CSIR for his research fellowship.
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