Tricyclic flavonoids with 1,3-dithiolium substructure

Article abstract of DOI:10.3762/bjoc.8.226

The synthesis of new 3-dithiocarbamic flavonoids has been accomplished by the reaction of the corresponding 2-hydroxyaryl dithiocarbamates with aminals. These flavonoids were obtained as a mixture of diastereoisomers, the anti isomer being the major one. The heterocyclization of these compounds provided novel tricyclic flavonoids bearing a 1,3-dithiolium-2-yl ring fused at the 3,4-carbon positions of the benzopyran moiety.

Full text of DOI:10.3762/bjoc.8.226

Tricyclic flavonoids with 1,3-dithiolium substructure
Lucian G. Bahrin*1,2, Peter G. Jones3 and Henning Hopf2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1999–2003.
1Department of Chemistry, “Al. I. Cuza” University of Iasi, 11 Carol I
Bv., RO-700506 Iasi, Romania, 2Institute of Organic Chemistry,
Technical University of Braunschweig, Hagenring 30, D-38106
Braunschweig, Germany and 3Institute of Inorganic and Analytical
Chemistry, Technical University of Braunschweig, Hagenring 30,
D-38106 Braunschweig, Germany
doi:10.3762/bjoc.8.226
Received: 27 August 2012
Accepted: 18 October 2012
Published: 16 November 2012
Associate Editor: P. R. Hanson
Email:
Lucian G. Bahrin* - l.bahrin@tu-braunschweig.de
© 2012 Bahrin et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aminals; benzopyrans; dithiocarbamates; dithiolium salts; flavonoids
Abstract
The synthesis of new 3-dithiocarbamic flavonoids has been accomplished by the reaction of the corresponding 2-hydroxyaryl
dithiocarbamates with aminals. These flavonoids were obtained as a mixture of diastereoisomers, the anti isomer being the major
one. The heterocyclization of these compounds provided novel tricyclic flavonoids bearing a 1,3-dithiolium-2-yl ring fused at the
3,4-carbon positions of the benzopyran moiety.
Introduction
The great diversity in physical, chemical and biochemical prop- Figure 1) leads to a substantial rise in the binding affinity for
erties of flavonoids gives them the ability to influence the bio- estrogen receptor β. Further improvements in binding selec-
logical activity of plants, microbes and animals [1-3]. tivity were obtained by combining the modifications performed
Flavonoids are known to be good antioxidants and this is on the C ring with modifications performed on the A ring, e.g.
believed to be the most probable mechanism of protection that 2, Figure 1 [8].
these compounds offer against conditions such as cancer or
cardiovascular disease [4].
Extracts from Hematoxylum campechianum and Caesalpinia
sappan are known to be effective in the treatment of various
SERBAs, or selective estrogen receptor β agonists, are conditions, such as diarrhea, dysentery, dyspepsia, leucorrhea,
benzopyran derivatives that interact with estrogen receptor and diabetic complications [9,10]. The main components of H.
subtypes α and β. The interest in this type of compound led to campechianum and C. sappan are hematoxylin (3, Figure 1) and
the synthesis of derivative 1, a selective estrogen receptor β brazilin; the basic structures of the two contain a 3,4-cycloalkyl-
agonist (SERBA-1, Figure 1) [5]. Studies that focus on the fused benzopyran unit. In addition to this, they are known to
structure–activity relationship were reported [6,7]. It was shown possess anti-inflammatory activity, inhibit the lens-aldose
that a cyclopentane ring at the 3,4-carbon positions (labeled C, reductase, and decrease the blood glucose level [11,12]. More-
1999

Beilstein J. Org. Chem. 2012, 8, 1999–2003.
Figure 1: Polycyclic flavonoids.
over, compound 3 was shown to inhibit HIV-1 integrase tions of the benzopyran moiety, utilizing the heterocyclization
[13,14]. of corresponding 3-substituted dithiocarbamic flavonones.
Several molybdenum and tungsten oxobisdithiolene complexes Results and Discussion
have been synthesized from a tricyclic flavonoid bearing a 1,3- The treatment of several dithiocarbamates of type 4 with
dithiolium-2-yl unit as C ring [15]. These complexes have been aminals has been reported to provide new substituted flavano-
electrochemically investigated to provide a better under- nes and related 4-chromanones [16]. Based on this study, we
standing of enzymatic activities in thermophilic and hyperther- decided to investigate the synthesis of new flavonoids bearing a
mophilic organisms.
1,3-dithiolium-2-yl ring fused at the 3,4-carbon positions of the
benzopyran core. The reaction of dithiocarbamates 4 with
This paper outlines the synthesis of novel tricyclic flavonoids aminals 5 provided 3-substituted dithiocarbamic flavanones 6 as
bearing a 1,3-dithiolium-2-yl ring fused at the 3,4-carbon posi- a mixture of diastereoisomers (Scheme 1, Table 1). The analyt-
Scheme 1: The synthesis of flavonoids 6 and 7.
Table 1: Flavonoids 6 and 7.
6, 7a
R1
R2
R3–N–R3
R4
Yields for 6, (%)
Yields for 7, (%)
a
b
H
H
H
88
83
73
60
H
H
OMe
c
d
e
f
H
Br
Br
Br
I
H
H
H
Br
I
NEt2
NEt2
NEt2
NEt2
NEt2
NEt2
OMe
Cl
H
60
71
81
62
64
87
76
71
64
80
80
65
H
g
h
H
I
I
Cl
a7g and 7h prepared in the presence of P2O5/MeSO3H (1:10) mixture.
2000

Beilstein J. Org. Chem. 2012, 8, 1999–2003.
ical and spectroscopic data are in agreement with the structures. the R2 substituent was recorded for the anti isomers. The
2-Hydroxyphenacyl dithiocarbamates 4 are known compounds replacement of the hydrogen atom at C8 by a bulky bromine or
and were prepared following the reported experimental pro- iodine atom induces a decrease of the 3JH2-H3 coupling constant
cedures [16-19]. Aminals 5 were synthesized according to the by about 2 Hz (6f–h).
literature procedures [20,21].
The structural information provided by the NMR data has been
Although the original short synthetic communication on unambiguously corroborated by X-ray analysis. The structures
flavonoids of type 6 [16] did not mention the existence of dia- of the anti isomers of flavonoids 6a and 6b are presented in
stereoisomers, we always identified an inseparable mixture of Figure 3 and Figure 4, respectively.
two diastereoisomers. Each isomer could be identified,
however, by their different NMR chemical shifts and coupling
constants of the H-2 and H-3 hydrogen atoms (6′ and 6″,
Figure 2). Furthermore, a major isomer was identified for all
flavonoids 6a–i. We therefore decided to investigate the struc-
tures of the two diastereoisomers, together with the influence of
substituents on their ratio. In principle, the two isomers could
have the hydrogen atoms at the 2 and 3 positions directed either
to opposite sides or to the same side of the benzopyrane ring.
The relative orientation of the two hydrogen atoms would, of
course, be expected to have an influence on the magnitude of
their coupling constants. Moreover, it is reasonable to assume
that the most stable isomer is that with an anti orientation of the
two hydrogen atoms (e.g., 6′, Figure 2).
Figure 3: Molecular structure of flavonoid 6a in the solid state. Ellip-
soids represent 50% probability levels. Torsion angle
C(11)–C(2)–C(3)–S(1): −59.19(14)°.
Figure 2: Diastereoisomers of flavonoids 6.
The coupling constants and diastereoisomeric ratios of
flavonoids 6 are presented in Table 2. Data analysis indicates
that the highest diastereoisomeric ratios are obtained for 6a and
6b, i.e., the flavonoids with an N-morpholinyl carbodithioate
substituent. Although no significant influence of the
substituents on 3JH2-H3 coupling constants of syn isomers was
recorded, an unexpected variation of the coupling constant with
Figure 4: Molecular structure of flavonoid 6b in the solid state. Ellip-
soids represent 50% probability levels. Torsion angle
C(21)–C(2)–C(3)–S(1): 59.72(11)°.
Table 2: Coupling constants and diastereoisomers ratio of flavonoids 6.
6
a
b
c
d
e
f
g
h
3JH2-H3 anti (Hz)
3JH2-H3 syn (Hz)
anti/syn ratio
9.3
9.8
9.3
9.5
9.5
7.6
7.2
7.8
4.0
4.3
4.3
4.0
4.2
4.0
4.1
3.8
86:14
77:23
73:27
72:28
69:31
65:35
64:36
69:31
2001

Beilstein J. Org. Chem. 2012, 8, 1999–2003.
The main synthetic approach for various substituted 1,3-dithi-
olium-2-yl cations consists of the cyclization of phenacyl
carbodithioates by using acid as catalyst. The heterocyclization
of compounds 6 should, hence, provide new tricyclic fused
flavonoids 7 by using an appropriate mixture of acids, as
described above (Scheme 1, Table 1). Using a concentrated
sulfuric acid/glacial acetic acid (1:3 v/v) mixture [22-24] the
cyclization of dithiocarbamates 6a–f takes place under mild
reaction conditions. By heating the reaction mixture at 80 °C
a homogeneous solution was obtained, which contains the
corresponding 1,3-dithiolium ions. The addition of 70%
perchloric acid to the cooled solution, followed by water
yielded perchlorates 7a–f, isolated as white crystalline
products in good to excellent yields (60–80%). Attempts
to cyclize N,N-dialkyldithiocarbamates 6g and 6h by using
the above-mentioned or other common cyclization agents,
according to the literature [25-27], led to degradation of the
substrates, often accompanied by loss of molecular iodine.
A literature survey revealed that a P2O5/CH3SO3H (1:10,
m/v) mixture may be the cyclization agent of choice to obtain
1,3-dithiolium salts 7g and 7h as pure compounds and in
high yields [28,29]. Thus, a suspension of 6g or 6h in
three parts of the ‘‘superacid’’ mixture was stirred at room
temperature for 30 min to give a solution that contained the
Figure 5: Molecular structure of flavonoid 7a in the solid state. Ellip-
soids represent 50% probability levels.
corresponding 1,3-dithiolium cation. Addition of 70% Conclusion
perchloric acid and methyl acetate to this solution yielded The synthesis of 3-dithiocarbamic flavonoids has been accom-
perchlorates 7g and 7h as white crystalline products in 65–80% plished by the reaction of the corresponding 2-hydrox-
isolated yield.
yphenacyl dithiocarbamates with aminals. Under strongly acidic
conditions these compounds provide novel tricyclic, fused
The structure of these charged tricyclic fused flavonoids was flavonoids with a 1,3-dithiol-2-yl substructure. The reactivity of
unambiguously proved by X-ray analysis. The structure of the latter derivatives could open the way for the synthesis of
tricyclic flavonoid cation 7a is presented in Figure 5. Structures new flavonoids with potential biological activities.
of the perchlorate salts proved to be disordered, so the
tetraphenylborate anion was used instead. The bond length
Supporting Information
C20–N21, 1.311(2) Å, corresponds to a double bond and thus to
a formal positive charge at the nitrogen atom. Similarly, C3–C4,
Supporting Information File 1
at 1.342(2) Å, is also a (marginally lengthened) double bond.
The C–S bond lengths in the five-membered ring are approxi-
mately equal [1.727(1) – 1.746(1) Å].
Experimental and X-ray spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-226-S1.pdf]
The new 1,3-dithiolium cations are particularly prone to nucle-
ophilic attack at their 2-positions [30]. This behavior opens the
way for the synthesis of various substituted 1,3-dithiolic rings,
especially those with a 2-ylidene moiety resulting from a
C-nucleophile attack. Furthermore, by using oxygen, sulfur,
phosphorus, or nitrogen nucleophiles, interesting and novel
structures can in principle be obtained [31]. The above combi-
nation of the chemistry of 1,3-dithiol-2-yl cations and the bio-
logical properties of flavonoids may provide new compounds
with interesting properties.
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