Catalyst-free Mannich reaction of hydroxyanthraquinone: Facile access to emodin Mannich bases and anthraoxazines

Article abstract of DOI:10.1016/j.tetlet.2013.03.059

A simple and efficient method for derivatization of hydroxyanthraquinone natural product emodin through catalyst-free Mannich reaction is described. The method allows the modification of emodin skeleton at 2-position. This new derivatization strategy to emodin provides a clear advantage over traditional approaches, due to its easy operation and efficiency that does not involve the protection and deprotection.

Full text of DOI:10.1016/j.tetlet.2013.03.059

Tetrahedron Letters 54 (2013) 2802–2805
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free Mannich reaction of hydroxyanthraquinone: facile access
to emodin Mannich bases and anthraoxazines
⇑
⇑
Li-Ming Zhao , Li-Ming Zhang, Feng-Yan Ma, Xiang-Shan Wang, Hai-Shan Jin
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116,
Jiangsu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method for derivatization of hydroxyanthraquinone natural product emodin
through catalyst-free Mannich reaction is described. The method allows the modification of emodin skel-
eton at 2-position. This new derivatization strategy to emodin provides a clear advantage over traditional
approaches, due to its easy operation and efficiency that does not involve the protection and
deprotection.
Received 10 January 2013
Revised 11 March 2013
Accepted 15 March 2013
Available online 26 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Emodin
Mannich reaction
Catalyst-free
The synthesis of diverse libraries is an important activity in the
drug discovery.1 Using natural products as starting scaffolds to ac-
cess diverse libraries is particularly attractive because of the rich
structural diversity and complexity of natural products.2 Owing
to the diverse biological activities and chemical properties, emo-
din, a hydroxyanthraquinone natural product, has received consid-
Mannich reaction is among the most useful carbon–carbon
bond formation reactions in organic synthesis. Most of the current
Mannich reactions are focused on the condensation of enolizable
ketones with formaldehyde and amines. Few examples of Mannich
reaction of phenols and naphthols have also been reported.10 In
contrast, there are only limited reports on hydroxyanthraquinon-
es.11 As a continuing interest in the development of new carbon–
carbon bond formation reactions,12 we decide to explore the Man-
nich reaction of hydroxyanthraquinones using emodin as the start-
ing compound. Herein, we present a highly efficient, simple work-
up, and catalyst-free synthesis of a wide range of emodin Mannich
bases as potential antitumor agents and building blocks for more
complex antitumor anthraquinones.
We initially selected benzaldehyde 2a as a model substrate and
attempted the condensation with emodin 1 and dimethylamine 3a
in H2O at 65 °C under catalyst-free conditions for 24 h (Table 1). As
expected, the emodin Mannich base 4a was produced, but the yield
was low (entry 1). We attributed it to the low solubility of emodin
and benzaldehyde in H2O. Some organic solvents such as DMF (en-
try 2), EtOH (entry 3), and dioxane (entry 6) were thus screened
and dioxane was proven to be the most effective, providing prod-
uct 4a in 76% yield with complete consumption of starting mate-
rial. Next, we studied the influence of the reaction temperature.
Carrying out the reaction at room temperature resulted in a lower
yield. Prolonged reaction time had no further effect (entry 4).
Increasing the temperature to 90 °C decreased the yield and also
led to the recovery of emodin 1 (entry 5) presumably due to the
volatility of dimethylamine 3a at an elevated temperature. To ver-
ify our assumption, we performed the reaction with 1 equiv
dimethylamine 3a at 65 °C, and a similar result was observed with
erable attention as
a promising candidate for new drug
development.3 Many emodin derivatives have been synthesized
in order to get less toxic and more potent antitumor agents. How-
ever, most modifications on the emodin structure are mainly fo-
cused on the hydroxyl group and methyl group.4 On the other
hand, a number of emodin based natural products with substitu-
ents at the 2- and/or 7-position are known to display various bio-
logical activities such as variecolorquinones A, which exhibits good
antitumor effects,5 aurantio-obtusin, a potent rat lens aldose
reductase (RLAR) inhibitor with IC50 value of 13.6
l
M,6 2-geranyl-
M,7 and
emodin, a potent antimalarial agent with IC50 value of 5.3
l
laurenquinone A, a potent antibacterial agent.8 (Fig. 1)
Based on this observation, we have synthesized a series of 7-
substituted O-trimethyl emodin and screened their antitumor
activities (Fig. 2). Unfortunately, most of the newly synthesized
derivatives showed lower antitumor activity than emodin.9 We
suspected that the protection of the hydroxyl group as the methyl
ether might result in a barrier to intercalation of the anthraquinone
ring with DNA, and we decided to investigate an alternative elab-
oration of emodin that does not involve the protection of the hy-
droxyl group.
⇑
Corresponding authors. Tel.: +86 516 83403165; fax: +86 516 83536977.
E-mail addresses: lmzhao@jsnu.edu.cn (L.-M. Zhao), hsjin@jsnu.edu.cn (H.-S. Jin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.059

L.-M. Zhao et al. / Tetrahedron Letters 54 (2013) 2802–2805
2803
OMe O
O
OH
OMe O
OH
O
OH
O
O
OH
MeO
MeO
OH
Me
O
OH
OH
HO
Me
HO
Me
Me
O
emodin
variecolorquinones A
aurantio-obtusin
Me
OH
O
OH
O
Me
Me
OH
O
O
OH
Me
Me
OMe
Me
HO
HO
2-geranylemodin
Figure 1. Biologically active emodin and emodin based natural products.
O
laurenquinone A
thenaldehyde 2m and nicotinaldehyde 2n, providing the corre-
sponding products 4m and 4n in 71% and 74% yields, respectively
(entries 12 and 13). The aliphatic aldehyde 2o is also compatible
and generates product 4o in 67% yield (entry 14). The structure
of product 4a was unequivocally established by X-ray analysis
(Fig. S1 in the Supplementary data).
OMe O
O
OMe
O
R
O
N
N
MeO
Me
F
Figure 2. Structure of 7-substituted O-trimethyl emodin derivatives.
Inspired by these positive results, we were subsequently inter-
ested in exploring other amines instead of dimethylamine. First,
we attempted to extend this aminoalkylation to aniline and form-
aldehyde. To our surprise, the reaction generated a new compound.
The unexpected appearance of two different proton signals of CH2
groups attached to the heteroatom (e.g., 1H NMR: 5.66 and
4.66 ppm) indicated that it was not a simple emodin Mannich base
from formaldehyde and aniline. After careful analysis of the 13C NMR
and HRMS, the new compound was finally assigned as 3,4-dihydro-
5,7-dihydroxy-9-methyl-3-phenyl-2H-anthra[2,3-e][1,3]oxazine-
6,11-dione 5a. This structure was further confirmed by X-ray
crystallography. The formation of 5a can be rationalized by the
condensation of emodin with formaldehyde and amine to give
the expected Mannich base 4p, in which the amino alcohol would
subsequently condense with the second formaldehyde to afford
the 1,3-oxazine ring (Scheme 1).
the reaction using 2 equiv dimethylamine 3a at 90 °C (entry 7). It is
disappointing that increasing the amount of dimethylamine from 2
to 4 equiv dropped the yield and afforded some unidentified
byproducts (entry 9). Therefore, conducting the reaction in dioxane
at 65 °C for 24 h with the 1:2:2 mol ratio of emodin, aldehyde, and
dimethylamine is the optimal condition.
Having defined an effective condition for the Mannich reaction,
we then explored the substrate scope with other aldehydes includ-
ing substituted aromatic aldehydes, hetero, and aliphatic alde-
hydes (Table 2). To our delight, a wide range of substituted
benzaldehydes, such as o-fluoro, m-fluoro, p-fluoro, p-bromo, p-ni-
tro, 2,4-dichloro, 3,5-dichloro, 3,4-dimethyl, p-methyl, o-methoxyl,
and p-formyl derivatives, reacted smoothly with emodin 1 afford-
ing the corresponding emodin Mannich bases 4b–4l in 56–83%
yields (entries 1–11). Apparently, the substituents in the aryl ring
have no significant influence on the product formation. This
reaction is also applicable to heterocyclic aldehydes such as 2-
Owing to the importance of 1,3-oxazine moiety in biological
systems,13 we turned our attention to investigate other primary
amines. We were gratified to find that other primary amines,
such as methylamine, also reacted smoothly with emodin 1 and
Table 1
Optimization of reaction conditions
OH
O
O
OH Ph
OH
O
OH
catalyst-free
solvent
NMe2
OH
PhCHO + NHMe2
+
Me
Me
OH
O
3a
2a
4a
1
Entry
Solvent
T (°C)
Ratioa
t (h)
4ab (%)
Recovery of emodinb (%)
1
2
3
4
5
6
7
8
9
H2O
DMF
EtOH
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
65
65
65
rt
90
65
65
65
65
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:1
1:1:2
1:2:4
24
24
24
72
71
24
60
60
24
22
40
63
27
22
76
42
41
57
Trace
Trace
28
57
49
Trace
45
27
Trace
a
Ratio sequence: emodin/aldehyde/dimethylamine.
Isolated yield.
b

2804
L.-M. Zhao et al. / Tetrahedron Letters 54 (2013) 2802–2805
Table 2
Scope of the emodin Mannich reaction with different aldehydes
OH
O
OH
OH
O
O
OH
R
65 °C
NMe2
+
RCHO
+
NHMe2
dioxane
Me
OH
Me
OH
O
2
3a
4
1
Entry
Aldehyde
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2-Fluorobenzaldehyde 2b
3-Fluorobenzaldehyde 2c
4-Fluorobenzaldehyde 2d
4-Bromobenzaldehyde 2e
4-Nitrobenzaldehyde 2f
2,4-Dichlorobenzaldehyde 2g
3,5-Dichlorobenzaldehyde 2h
3,4-Dimethylbenzaldehyde 2i
4-Methylbenzaldehyde 2j
2-Methoxylbenzaldehyde 2k
Terephthalaldehyde 2l
2-FC6H4
3-FC6H4
4-FC6H4
4-BrC6H4
4-NO2C6H4
2,4-Cl2C6H3
3,5-Cl2C6H3
3,4-(CH3)2C6H3
4-CH3C6H4
2-CH3OC6H4
4-CHOC6H4
2-Thienyl
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
81
64
69
77
73
66
72
56
83
64
71
71
74
67
2-Thenaldehyde 2m
Nicotinaldehyde 2n
Cyclopropanecarbaldehyde 2o
3-Pyridinyl
Cyclopropyl
OH
O
OH
OH
O
OH
Ph
65 °C
N
+
HCHO
+
PhNH2
H
dioxane
Me
OH
Me
OH
O
O
4p
1
OH
O
O
OH
HCHO
-H2O
Ph
N
Me
O
5a
X-ray (H omitted)
Scheme 1. Reaction of emodin with formaldehyde and aniline.
OH
O
O
OH Ph
Me
N
Me
O
Ph
5b
X-ray (H omitted)
Figure 3. Crystal structure of product 5b from the Mannich reaction between emodin, benzaldehyde, and methylamine.
benzaldehyde to form the anthraoxazine in moderate yield (68%)
(Fig. 3). To the best of our knowledge, emodin incorporating
oxazine fragments in the molecule has never been obtained
before.
In conclusion, we have developed an efficient catalyst-free
hydroxyanthraquinone Mannich reaction using emodin as the
starting material. This one-pot procedure allows convenient access
to two new classes of molecules depending on the choice of
amines. Furthermore, this new derivatization strategy to emodin
provides a clear advantage over traditional approaches (modifica-
tion of the hydroxyl group and methyl group), due to its ease of
operation and efficiency that does not involve the protection and
deprotection. We believe that the methodology described herein
provides
a practical method to derivatize and functionalize

L.-M. Zhao et al. / Tetrahedron Letters 54 (2013) 2802–2805
2805
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
059.
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