In the present Letter, the efficient stereoselective synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones by means of one-pot multicomponent reactions using 2-hydroxy-1,4-naph
Trang 1Expedient stereoselective synthesis of new dihydropyrano- and
dihydrofuranonaphthoquinones
a
Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, CauGiay, Hanoi, Vietnam
b
SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
c
Hanoi University of Science, 19-Le Thanh Tong str., Hoan Kiem, Hanoi, Vietnam
a r t i c l e i n f o
Article history:
Received 30 January 2015
Revised 6 March 2015
Accepted 17 March 2015
Available online xxxx
Keywords:
Pyranonaphthoquinones
Furanonaphthoquinones
Multicomponent reactions
2-Hydroxy-1,4-napthoquinones
a b s t r a c t
Heterocyclic naphthoquinones represent valuable scaffolds in medicinal chemistry In the present Letter, the efficient stereoselective synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones by means of one-pot multicomponent reactions using 2-hydroxy-1,4-naphthoquinone, an aromatic aldehyde and ethyl 4,4,4-trifluoroacetoacetate or a pyridinium bromide, respectively, is described
Ó 2015 Elsevier Ltd All rights reserved
Introduction
Heterocyclic naphthoquinones are widely distributed in nature,
where they contribute to several biochemical processes in bacteria,
fungi and plants Because of their pronounced biological and
pharmacological properties, these scaffolds have attracted
con-siderable attention from organic and medicinal chemists.1 For
example, a-lapachone 1 and b-lapachone 2, originally isolated
from the bark of Tabebuia sp., are known to exhibit a wide range
of biological activities including anticancer, antibacterial,
properties,2 and also their non-natural furano analogues 3 and 4
are known to show cytotoxic activity (Fig 1).3 Other examples
include nanaomycin A 5, isolated from Streptomyces rosa notoensis,
with antibiotic and antifungal properties,4psychorubin 6, a
cyto-toxic pyranonaphthoquinone exhibiting antitumor, antibiotic and
antileishmanial properties isolated from the roots of Psychotria
Kigelia pinnata with antitumor properties,6and synthetic
furanon-aphthoquinone 8 displaying antileishmanial activity.7
It is evident that the broad biological relevance of heterocyclic
naphthoquinones inspired many chemists and prompted them to
develop approaches towards novel analogues, often within the framework of bioactive compound development.8
In continuation of our synthetic efforts related to functionalized heterocyclic naphthoquinones,9the synthesis of new dihydropyr-ano- and dihydrofuranonaphthoquinones is investigated in the present Letter starting from 2-hydroxy-1,4-naphthoquinone using one-pot multicomponent reactions (MCRs) The deployment of 2-hydroxy-1,4-naphthoquinone as a building block in MCRs has been the topic of many studies, often involving the use of aromatic aldehydes as reaction partners.10 In general, the application of multicomponent strategies has become very popular in recent years as they provide high structural diversity through multiple
structure-activity relationship studies concerning functionalized heterocyclic naphthoquinones have shown that the introduction
of chemically diverse side chains to the heterocyclic ring can enhance the biological activities of these molecules,12making the synthesis of new naphthoquinone-fused heterocycles through MCRs a relevant challenge in modern organic and medicinal chemistry
Results and discussion The synthetic strategy used in this study towards new hetero-cyclic naphthoquinones is based on the above-described building
http://dx.doi.org/10.1016/j.tetlet.2015.03.071
0040-4039/Ó 2015 Elsevier Ltd All rights reserved.
⇑ Corresponding author Tel.: +84 917683979.
E-mail address: ngvtuyen@hotmail.com (T Van Nguyen).
Contents lists available atScienceDirect
Tetrahedron Letters
j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / t e t l e t
Trang 2block approach starting from 2-hydroxy-1,4-naphthoquinone via
multicomponent reactions First, the synthesis of a number of
dihydropyranonaphthoquinones using aromatic aldehydes, ethyl
4,4,4-trifluoroacetoacetate and ammonium acetate, is described
Subsequently, the preparation of a variety of new
dihydrofuranon-aphthoquinones is pursued using pyridinium bromides and
aro-matic aldehydes
For the synthesis of new dihydropyranonaphthoquinones 9a–f,
a recently developed tandem multicomponent reaction starting
some minor adaptations in the reaction conditions (tBuOH was
used as solvent instead of EtOH and NH4OAc was used instead of
a NH4OAc/AcOH mixture) (Scheme 1,Table 1) By using an excess
of ammonium acetate instead of a NH4OAc/AcOH mixture in a
cat-alytic amount, the reaction mechanism is assumed not to proceed
via acid catalysis but possibly through the formation of a
triflu-orinated enamine, formed in situ by imination of b-keto ester 12
with ammonium acetate.14However, it should be noted that both
approaches seem comparable with regard to product yield and
efficiency In this way, six new dihydropyranonaphthoquinones
9a–f were obtained in 53–86% yield as single diastereoisomers.15
The relative stereochemistry of compound 9 was confirmed by
means of X-ray single crystal analysis and corroborated the
stereo-chemistry as described in the literature.13The use of
2-hydroxy-benzaldehyde and indole-3-carbaldehyde in this approach did
not lead to the premised derivatives
In order to provide a convenient entry into the synthesis of the
lower homologues of the above-mentioned
dihydropyranonaph-thoquinones, the preparation of dihydrofuranonaphthoquinones
14 as novel scaffolds was contemplated in the next part
The synthesis of these novel furanonaphthoquinones 14a–l was
conducted using a one-pot multicomponent reaction, for which
tri-ethylamine was added to a solution of
2-hydroxy-1,4-naphtho-quinone 10, aromatic aldehyde 15 and pyridinium bromide 16 in
tBuOH The mixture was heated under reflux for 4 h, resulting in
the selective formation of dihydrofuranonaphthoquinones 14a–l
in 53-76% yield as single diastereoisomers (Scheme 2,Table 2).16
By varying the aromatic aldehyde and pyridinium bromide, 12
structure In the1H NMR spectrum of compound 14a, two protons
of the dihydrofuran moiety were seen as doublets at d = 4.96 and 6.09 ppm with a vicinal coupling constant of 5.5 Hz, indicating that the thermodynamically more stable trans diastereoisomer is formed.17X-ray analysis was then performed on dihydrofuranon-aphthoquinone 14b to secure the relative stereochemistry of these new molecular frameworks (Fig 2) As demonstrated inTable 2, a set of 12 new derivatives 14a–l was prepared through variation of the substitution pattern of the starting aldehyde 15 and pyri-dinium bromide 16 In that respect, both electron-donating and electron-withdrawing substituents present on the phenyl moieties were selected to assess their influence on the reaction outcome However, no major effects were observed, leading to comparable yields in all cases
A possible mechanistic explanation for this multicomponent reaction starts with a Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone 10 with aromatic aldehydes 15, followed by dehydration resulting in the formation of 1,2,3,4-tetrahydro-1,2,4-naphthalenetriones 18 The next step is a Michael addition
of pyridinium ylides 19, formed in situ by deprotonation of pyri-dinium bromides 16 by triethylamine, across Michael acceptors
18 The obtained naphthoquinones 20/21 undergo a cyclization
to produce the desired substituted dihydrofuranonaphthoquinones
O
O
R 1 H
O + 1.2 equiv. F3 C
O OEt
O 1.2 equiv.
3 equiv NH 4 OAc
tBuOH, Δ, 4 h
12 13
O O
O
R 1
OH
CF 3
OEt O
9a-f (53-86%)
OH
Scheme 1 Synthesis of dihydropyranonaphthoquinones 9a–f.
Table 1 Preparation of ethyl 2-hydroxy-5,10-dioxo-2-trifluoromethyl-3,4,5,10-tetrahydro-2H-benzo[g]chromene-3-carboxylates 9
Entry R 1
Compound (yield) a
3 3,4-OCH 2 O–C 6 H 3 9c (86%)
6 1-Acetyl-indol-3-yl 9f (65%)
a
After purification by column chromatography (SiO 2 ).
O O
O
O O
O O
O
OH
O O
O OH
O O
O
N N N
OH O
O
O
7
Figure 1 Examples of biologically active heterocyclic naphthoquinones.
Trang 314 (Scheme 3) The proposed mechanism was further supported
through analysis of the reaction mixtures using LC–MS providing
evidence for the presence of intermediates 18 and 20/21, although
other alternative routes cannot be ruled out completely No major
effects of the substrate scope on the yields could be observed, and
the proposed mechanism seems to be consistent with the use of
aromatic aldehydes and aromatic pyridinium bromides
In conclusion, the efficient diastereoselective synthesis of a variety of functionalized dihydropyrano- and dihydrofuranonaph-thoquinones has been described using one-pot multicomponent reactions These heterocyclic naphthoquinones could represent interesting new structures within the pursuit of biologically active compounds
Acknowledgments The authors are indebted to the Vietnamese National Foundation for Science and Technology Development (NAFOSTED, code: 104.01-2013.27) and to Ghent University—Belgium (BOF) for financial support
References and notes
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O
O
OH
R 1
O H
O
O
O
H R1
OH -H2 O
O
O
O
N O
R 2
Br
N O
Et3N
-Et 3 HNBr
R 1
O
O
OH
R 1 N O
R 2
O
OH
O
R 1 N O
R 2
O
O
O
R 1 R 2
O
14
20 21
Scheme 3 Proposed mechanism for the formation of compounds 14.
O
O
R 1 H
O + 1.2 equiv.
N O
R 2
Br
1.2 equiv.
+
16
O
O
O 1.2 equiv Et 3 N
tBuOH, Δ, 4 h
14a-l (53-76%)
OH
R 1
O
R 2
Scheme 2 Synthesis of dihydrofuranonaphthoquinones 14a–l.
Table 2
Preparation of 2,3-dihydronaphtho[2,3-b]furan-4,9-diones 14
Entry R 1
R 2
Compound (yield) a
1 C 6 H 5 C 6 H 5 14a (69%)
2 C 6 H 5 3-NO 2 –C 6 H 4 14b (67%)
3 C 6 H 5 4-NO 2 –C 6 H 4 14c (69%)
4 C 6 H 5 4-F–C 6 H 4 14d (66%)
5 4-Br–C 6 H 4 3-NO 2 –C 6 H 4 14e (62%)
6 3-Br–C 6 H 4 C 6 H 5 14f (53%)
7 3-Br–C 6 H 4 3-NO 2 –C 6 H 4 14g (76%)
8 4-Cl–C 6 H 4 4-F–C 6 H 4 14h (65%)
9 4-MeO–C 6 H 4 C 6 H 5 14i (60%)
10 4-MeO–C 6 H 4 3-NO 2 –C 6 H 4 14j (70%)
11 3-MeO–C 6 H 4 4-F–C 6 H 4 14k (68%)
12 Naphth-2-yl C 6 H 5 14l (70%)
a
After purification by column chromatography (SiO 2 ).
O
O
O
14b
O
NO 2
Figure 2 X-ray crystal structure of compound 14b.
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15 General procedure for the synthesis of dihydropyranonaphthoquinones 9: a mixture of 2-hydroxy-1,4-naphthoquinone 10 (1 equiv), aromatic aldehyde 11 (1.2 equiv), ethyl 4,4,4-trifluoroacetoacetate 12 (1.2 equiv) and ammonium acetate 13 (3 equiv) in tBuOH was heated under reflux for 4 h Then, the reaction mixture was extracted three times with EtOAc and the combined organic phases were washed with a saturated aqueous solution of NaHCO 3 , dried (MgSO 4 ) and evaporated in vacuo to afford the crude reaction mixture, which was purified by means of column chromatography on silica gel (n-hexane/EtOAc, 4/1) Ethyl (2S ⁄
,3S ⁄
,4R ⁄
)-2-hydroxy-4-(3-methoxyphenyl)-5,10-dioxo-2-trifluorome-thyl-3,4,5,10-tetrahydro-2H-benzo[g]chromene-3-carboxylate 9a: red-yellow solid, 65% yield Mp 130–133 °C IR (KBr):m3564; 3500; 2986; 2786; 1731; 1674; 1590; 1486; 1454; 1353; 1188; 1096; 986; 847; 729 cm 1 1 H NMR (CDCl 3 ,
500 MHz): d 8.12 (1H, d, J = 1.5, 7.0 Hz); 7.90 (1H, d, J = 1.0, 7.0 Hz); 7.66–7.72 (2H, m); 7.22 (1H, d, J = 8.0 Hz); 6.79 (1H, dd, J = 2.0, 8.0 Hz); 6.71 (1H, d,
J = 8.0 Hz); 6.68 (1H, d, J = 2.0 Hz); 4.35 (1H, d, J = 11.5 Hz); 4.12 (2H, q,
J = 7.0 Hz); 3.76 (3H, s); 3.15 (1H, d, J = 11.5 Hz); 1.07 (3H, t, J = 7.0 Hz); 13
C NMR (CDCl 3 , 125 MHz): d 182.3; 177.8; 172.1; 160.0; 150.7; 140.6; 134.3; 133.6; 131.8; 130.7; 130.1; 126.5; 126.4; 123.4; 122.7 (q, J = 285 Hz); 119.7; 113.3; 112.6; 94.4 (q, J = 33 Hz); 62.7; 55.2; 49.3; 40.1; 13.7 HRMS (ESI) [M+H] +
: Calcd for C 24 H 20 F 3 O 7 : 477.1156, Found: 477.1167.
16 General procedure for the synthesis of dihydrofuranonaphthoquinones 14: to a solution of 2-hydroxy-1,4-naphthoquinone 10 (1 equiv), aromatic aldehyde 15 (1.2 equiv) and pyridinium bromide 16 (1.2 equiv) in tBuOH was added 1.2 equiv of triethylamine at room temperature The mixture was heated under reflux for 4 h, followed by extraction (three times) with EtOAc The combined organic phases were washed with a saturated aqueous solution of NaHCO 3 , dried (MgSO 4 ) and evaporated in vacuo to afford the crude reaction mixture, which was purified by means of column chromatography on silica gel (n-hexane/EtOAc, 4/1).
(2R ⁄
,3R ⁄
)-2-Benzoyl-3-phenyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione 14a: yellow solid, 69% yield Mp 191–193 °C IR (KBr):m3451; 2931; 1693; 1630; 1584; 1446; 1362; 1191; 1060; 965; 859; 699 cm 1
1
H NMR (CDCl 3 ,
500 MHz): d 8.12 (1H, dd, J = 2.0, 7.5 Hz); 7.95 (1H, dd, J = 2.0, 7.5 Hz); 7.92 (2H, dd, J = 1.0, 8.5 Hz); 7.68–7.69 (2H, m); 7.63 (1H, t, J = 7.5 Hz); 7.48 (2H, t,
J = 8.0 Hz); 7.31–7.40 (5H, m); 6.09 (1H, d, J = 5.5 Hz); 4.96 (1H, d, J = 5.5 Hz).
13 C NMR (CDCl 3 , 125 MHz): d 190.1; 181.0; 177.5; 159.1; 139.4; 134.3; 133.2; 132.9; 131.6; 130.8; 129.3; 129.2; 129.1; 128.7; 128.4; 126.3; 126.2; 126.1; 91.4; 48.5 HRMS (ESI) [M+H] +
: Calcd for C 25 H 17 O 4 : 381.1121, Found: 381.1133.
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