The construction of polysubstituted aromatic core derivatives via a cycloaddition/oxidative aromatization sequence from quinone and β-enamino esters

Article abstract of DOI:10.1002/adsc.201300892

An unexpected strategy has been discovered for the construction of polysubstituted aromatic core derivatives from the reaction of quinones or N-substituted maleimides with b-enamino esters by a cycloaddition/oxidative aromatization sequence that provides products contrary to those delivered by the Nenitzescu reaction. The current method provides a highly favorable synthetic strategy for the efficient construction of important therapeutic agents containing polysubstituted aromatic core structures.

Full text of DOI:10.1002/adsc.201300892

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DOI: 10.1002/adsc.201300892
The Construction of Polysubstituted Aromatic Core Derivatives
via a Cycloaddition/Oxidative Aromatization Sequence from
Quinone and b-Enamino Esters
Yu-Jin Li,a,* Huan-Ming Huang,a Qing Ye,a Li-Fen Hou,b Wu-Bin Yu,a
Jian-Hong Jia,a and Jian-Rong Gaoa,*
a
Key Laboratory Breeding Base of Green Chemistry–Synthesis Technology, Zhejiang University of Technology, Hangzhou
310014, Peopleꢀs Republic of China
Fax : (+86)-0571-8832-0544; phone: (+86)-0571-8832-0891; e-mail: lyjzjut@zjut.edu.cn or gdgjr@zjut.edu.cn
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, Peopleꢀs Republic of China
b
Received: October 4, 2013; Published online: January 28, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300892.
Abstract: An unexpected strategy has been discov-
ered for the construction of polysubstituted aromat-
ic core derivatives from the reaction of quinones or
N-substituted maleimides with b-enamino esters by
a cycloaddition/oxidative aromatization sequence
that provides products contrary to those delivered
by the Nenitzescu reaction. The current method
provides a highly favorable synthetic strategy for
the efficient construction of important therapeutic
agents containing polysubstituted aromatic core
structures.
cancer, antibacterial, antimalarial, fungicidal, and an-
tiparasitic agents.[19] Based on the recent resurgence
of interest in the functionalization of quinone struc-
tures[20] and the application of b-enamino esters in or-
ganic synthesis,[21] we became interested in further ex-
ploring the reactions of b-enamino esters with qui-
nones.
During the course of our research in this area, an
unexpected product, diethyl 9,10-anthraquinone-1,3-
dicarboxylate (3a), was discovered involving the reac-
tion of 1,4-naphthoquinone (1a) with ethyl-3-(methyl-
amino)acrylate (2a) [Eq. (2)]. Contrary to similar
work reported by Menꢁndez et al. [Eq. (1)],[22] howev-
er, where the Nenitzescu reaction was used to obtain
fused indoles, our own work led to the formation of
a different product 3a, with the difference in the
products being attributed to the presence of an H
atom instead of a methyl group at the R2 position of
the b-enamino esters under the same conditions as re-
Keywords: cycloaddition; b-enamino esters; oxida-
tive aromatization; quinone; N-substituted male-
ACHTUNGTRENNUNGimides
b-Enamino esters are versatile intermediates, which ported by Menꢁndez (Table 1, entry 1).
are often used for the synthesis of heterocycles, and
Furthermore, among various kinds of naturally oc-
compounds of this class are also common pharmaco- curring substances, quinone derivatives are common
phores in a number of important medicinal agents.[1] and very important.[23] For example, rhein,[24] phys-
Furthermore, b-enamino esters are employed as key cion,[23d,25] aloe-emodin;[26] emodin[27] and chrysopha-
starting reagents for the synthesis of substituted pyra- nol[28] exhibit antifungal activity.[23d,29] Especially
zoles,[2] substituted aromatic amines,[3] substituted pyr- emodin, which is purified from the Chinese medicinal
roles,[4] 1,4-dihydropyridine derivatives,[5] functional- herb rhubarb, has inhibitory activity against ERK
ized
azaspiroACHTUNGTRENNUNG
[4,5]decatrienes,[8] 1,2,3-triazole derivatives,[9] Moreover, aloe-emodin might represent a conceptual-
pyrimidines,[6]
benzo[g]isoquinolines,[7]
2- phosphorylation in PC3 cells induced by EGF.[30]
indolequinones,[10] 2-substituted-1,4-quinones,[11] C- ly new lead antitumor drug taking into account its
glycosides,[12] 2-pyrrolidone derivatives,[13] 2-oxo- unique cytotoxicity profile and mode of action.[26a] Be-
[1,4]oxazinoACHTUNGTRENNUNG
[3,2-e]indoles,[14] 4-thioxopyrimidines,[15] sides, DMAC, aloesaponarin I and aloesaponarin II
and 5-hydroxyindole derivatives.[16]
also show good antibacterial activity (Figure 1).[31]
Based on this initial result and the significance of
Quinones represent one of the most widely distrib-
uted structural classes in nature,[17] and compounds these unexpected polysubstituted aromatic cores in
belonging to this class can be found in a large number related drugs, we became interested in developing
of important pharmacophores[18] associated with anti- a greater understanding of this reaction between 1,4-
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Yu-Jin Li et al.
Table 1. Initial evaluation of the reaction conditions.[a]
Entry
Solvent
Temperature
Additive
Yield of 3a [%][b]
Yield of 4 [%][b]
1
2
3
4
5
6
7
8
ethanol
CHCl3
CH2Cl2
toluene
CH3CN
CH3CN
CH3CN
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
808C
708C
608C
r.t.
CAN (0.05)
–
–
–
23
18
25
10
20
30
29
52
60
64
62
42
75
85
37
60
58
49
–
54
40
46
–
–
–
–
–
–
FeCl3 (1.0)
FeCl3 (0.1)
–
–
–
–
–
TBHP (1.0)
O2
N2
9
10
11
12
13
14
15
708C
708C
708C
–
–
–
[a]
Reaction conditions: the mixture of 1a (1.0 mmol) and 2a (3.0 mmol) in solvent (5.0 mL) was stirred for 6 h at the corre-
sponding temperature in an open flask.
Isolated yield.
[b]
Figure 1. Several important anthraquinone derivatives.
naphthoquinone and ethyl-3-(methylamino)acrylate work, we address these challenges and also optimize
with a view of determining the structure of any possi- the reaction conditions for this transformation with
ble polysubstituted aromatic core derivatives products the aim of developing a new aromatization method
and exploiting their synthetic potential. In the current from the b-enamino ester as the raw substrate that
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The Construction of Polysubstituted Aromatic Core Derivatives
Table 2. Scope of different b-enamino esters.
could potentially provide a rapid access to useful
polysubstituted aromatic core derivatives in a simple
and efficient manner, in contrast to those produced
by the Nenitzescu reaction. Herein, we describe the
details of our work in this area.
As shown in Table 1, the reaction between 1,4-
naphthoquinone 1a (1.0 mmol) and ethyl b-methyl-
ACHTUNGTRENNUNGaminoacrylate 2a (3.0 mmol) gave the unexpected
product 3a in low yields in a range of organic solvents,
including ethanol (23%), CHCl3 (18%), CH2Cl2
(25%), toluene (10%), and CH3CN (20%) under
reflux conditions for 6 h, with the coupling product 4
being isolated as a major by-product (Table 1, en-
tries 1–5). Pleasingly, the yield of 3a was slightly in-
creased by the presence of catalytic or stoichiometric
amounts of the Lewis acid FeCl3 (Table 1, entries 6
and 7). This result indicated that the acid catalyst was
useful for the cyclization process. The yield of 3a was
increased to 52% when HOAc was used as a solvent
(Table 1, entry 8), and an investigation of the reaction
temperature revealed that the yield could be in-
creased to 64% when the reaction was conducted at
708C in HOAc (Table 1, entries 8–12). To further im-
prove the efficiency of the reaction, we investigated
the addition of an oxidant to the reaction mixture.
Pleasingly, the addition of tert-butyl hydroperoxide
(1.0 equiv.) to the reaction mixture resulted in a signif-
icant increase in the yield of 3a to 75% (Table 1,
entry 13). Interestingly, product 3a was obtained in
85% yield when 1a and 2a were reacted under an
oxygen atmosphere (Table 1, entry 14). In contrast,
when the reaction was conducted under a nitrogen at-
mosphere, the yield of product 3a fell to 34%
(Table 1, entry 15).
With the optimized conditions in hand, we proceed-
ed to evaluate the substrate scope of this oxidative ar-
omatization using a range of different ethyl amino-
substituted acrylates. The same product 3a was ob-
tained in 62 and 73% yields when ethyl b-dimethyl-
[a]
Isolated yields.
ACHTUNGTRENNUNG
tries 1–3). A variety of different b-enamino esters ingly, when isobutyl methylaminoacrylate was em-
bearing structural variation in the ester groups was ployed as the b-enamino ester, the yield of the prod-
then reacted with 1,4-naphthoquinone 1a to give the uct was slightly reduced because of steric effects.
corresponding products 3a–c in good to excellent Based on these results, we were able to establish that
yields (Table 2, entries 1, 4 and 5).
the reaction proceeded smoothly with N-aryl-substi-
The application of the optimized reaction condi- tuted maleimides 1c–f and that electron-donating sub-
tions to 1,4-anthraquinone 1b proceeded efficiently stituents on the benzene ring favored the formation
with the b-enamino esters 2a–c to give the corre- of product 3. In comparison, the use of N-alkyl-substi-
sponding products 3d–f in good to excellent yields tuted maleimides resulted in lower yields because the
(Table 3, entries 1–3). Given the importance of N-sub- formation of some other by-products that could not
stituted phthalimide derivatives in pharmacochemis- be separated and characterized as they were not suffi-
try,[32] a wide range of N-substituted maleimides 1c–h ciently stable under acidic conditions (Table 3, en-
was also investigated under the optimized reaction tries 14–19).
conditions, and gave the corresponding oxidative aro-
On the basis of the results provided above, we have
matization products 3, albeit in slightly lower yields in tried the reaction of the isolated coupling product 4
the range of 35–71% (Table 3, entries 4–13). Interest- with ethyl b-methylaminoacrylate, but the product 3
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Yu-Jin Li et al.
Table 3. Scope of the current reaction for the formation of
3.
Table 3. (Continued)
[a]
Isolated yields.
was not obtained. To confirm the intermediates of
this reaction and elucidate the mechanism for the for-
mation of 3, the intermediate B was isolated and its
structure determined by NMR analysis (see the Sup-
porting Information).[33] Then we proposed a tentative
mechanism for this oxidative aromatization process
(Scheme 1).
Firstly, ethyl 3-hydroxyacrylate A was formed from
2a under acidic conditions,[34] with a subsequent cou-
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The Construction of Polysubstituted Aromatic Core Derivatives
velopment of milder reaction conditions are still de-
sired, we believe that this new protocol will provide
a platform for the development of new methods from
the b-enamino ester as the raw substrate for the prac-
tical construction of polysubstituted aromatic core de-
rivatives.
Experimental Section
Representative Procedure for the Synthesis of 3
A mixture of 1.4-naphthoquinone (1a, 1.0 mmol, 0.158 g,
1.0 equiv.), ethyl b-methylaminoacrylate (2a, 3.0 mmol,
0.387 g, 3.0 equiv.) and HOAc (5.0 mL) was stirred for 6 h at
708C under an atmosphere of oxygen. Upon completion of
the reaction, as determined by GC-MS and TLC, the mix-
ture was cooled to ambient temperature and the solvent was
removed under vacuum to give the crude product, which
was purified by column chromatography on silica gel using
CH2Cl2 as the eluent to give 3a as a yellow solid; yield:
0.300 g (84%): mp 156–1578C.
Scheme 1. Plausible reaction mechanism.
pling reaction between A and 2a giving rise to inter-
mediate B. Intermediate C was then formed through
a Diels–Alder reaction between 1a and B,[35] with
a subsequent oxidative aromatization giving rise to
product 3a under an oxygen atmosphere. Besides, the
by-product 4 was formed through an initial Michael
addition followed by sequential tautomerization to
the corresponding hydroquinone species and oxida-
tion by air (Scheme 2).[22]
In conclusion, we have developed an exciting new
strategy for the construction of polysubstituted aro-
matic core derivatives from the oxidative aromatiza-
tion reaction of quinones or N-substituted maleimides
with b-enamino esters under an oxygen atmosphere.
This novel protocol provides a rapid and efficient
access to biologically important polysubstituted aro-
matic core derivatives in a highly concise fashion. Al-
though detailed mechanistic descriptions and the de-
Acknowledgements
This work was supported by the Natural Science Foundation
of China (Grant no. 21176223), the National Natural Science
Foundation of Zhejiang (Grant no. LY13B020016), and the
Key Innovation Team of Science and Technology in Zhejiang
Province (Grant no. 2010R50018).
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Adv. Synth. Catal. 2014, 356, 421 – 427

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1
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Adv. Synth. Catal. 2014, 356, 421 – 427
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