Silicon-mediated highly efficient synthesis of 1,8-dioxo-octahydroxanthenes and their transformation to novel functionalized pyrano-tetrazolo[1,5-a] azepine derivatives

Article abstract of DOI:10.1016/j.cclet.2013.03.021

A facile and highly efficient protocol for the synthesis of 1,8-dioxo-octahydroxanthene derivatives was achieved through cascade Knoevenagel-Michael condensations and cyclo-dehydration reaction utilizing tetrachlorosilane (TCS) as catalyst under mild cond

Full text of DOI:10.1016/j.cclet.2013.03.021

Chinese Chemical Letters 24 (2013) 404–406
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Silicon-mediated highly efficient synthesis of 1,8-dioxo-octahydroxanthenes
and their transformation to novel functionalized pyrano-tetrazolo
[1,5-a] azepine derivatives
b,
Hanan A. Soliman a, , Tarek A. Salama
*
*
a Photochemistry Department, National Research Center, Dokki, Cairo 12622, Egypt
b Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile and highly efficient protocol for the synthesis of 1,8-dioxo-octahydroxanthene derivatives was
achieved through cascade Knoevenagel–Michael condensations and cyclo-dehydration reaction utilizing
tetrachlorosilane (TCS) as catalyst under mild conditions. Reaction of the titled compounds with TCS–
NaN3 to give novel functionalized pyrano[3,2-c]tetrazolo[1,5-a]azepine derivatives is also described.
ß 2013 Hanan A. Soliman, Tarek A. Salama. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Received 11 January 2013
Received in revised form 27 February 2013
Accepted 5 March 2013
Available online 18 April 2013
Keywords:
Tetrachlorosilane
1,8-Dioxo-octahydroxanthenes
Synthesis
Tetrazolo[1,5-a]azepines
1. Introduction
our interest in the utility of tetrachlorosilane (TCS) [14–19] in
organic synthesis, we report herein a facile and mild procedure for
The 1,8-dioxo-octahydroxanthenes are important oxygen
heterocycles which have various applications in the field of
medicinal chemistry and material science. They exhibit a broad
spectrum of biological activities, such as anti-inflammatory,
antibacterial, antiviral activities [1], and also find applications in
photodynamic therapy [2], luminescent sensors [3], fluorescent
materials [4], cosmeticsand pigments [5], and laser technologies [6].
Synthesis of 1,8-dioxo-octahydroxanthene is generally achieved
by the condensation of 5,5-dimethyl-1,3-cyclohexadione with
aromatic aldehydes using Lewis acid catalysts [7]. However, they
suffer from one or more drawbacks such as longer reaction times,
low yields, ease of availability of catalyst, involves cumbersome
preparation of catalysts and lack of selectivity. On the other hand,
tetrazoles have found numerous applications in medicinal
chemistry [8]. In particular, 1,5-disubstituted tetrazoles have
been described in the literature as HIV-protease inhibitors [9],
glucokinase activators [10], NAD(P)H oxidase inhibitors [11],
the synthesis of 1,8-dioxo-octahydroxanthene derivatives in
excellent yields through the reaction of dimedone with various
aromatic aldehydes in a tandem process including Knoevenagel
condensation, Michael addition and cyclo-dehydration using the
inexpensive and readily available tetrachlorosilane. Transforma-
tions of the prepared 1,8-dioxo-octahydroxanthene derivatives
into novel functionalized pyrano-bistetrazolo[1,5-a]azepine deri-
vatives were also accomplished through their reactions with
SiCl4/NaN3 [20–23].
2. Experimental
Typical procedure for the synthesis of 1,8-dioxo-octahydrox-
anthene derivatives: To a mixture of aldehyde (5 mmol) and
demidone (10 mmol) in ClCH2CH2Cl (20 mL), a catalytic amount of
SiCl4 (1 mmol, 0.12 mL) was added and the reaction mixture
stirred at 60–70 8C. On completion (the reaction was monitored by
TLC), the mixture was quenched with cold water, extracted with
CHCl3, dried over anhydrous MgSO4, the solvent was removed
under vacuum and the residue was recrystallized from EtOH to
give purified 3. The octahydroxanthenediones 3 are known
compounds and all spectroscopic data were in agreement with
literature.
hepatitis
C virus serine protease NS3 inhibitors [12], and
cyclooxygenase-2 (COX-2) inhibitors [13]. In conjunction with
* Corresponding authors.
E-mail addresses: tarek12_2@yahoo.com (H.A. Soliman), tasalama@yahoo.com
(T.A. Salama).
1001-8417/$ – see front matter ß 2013 Hanan A. Soliman, Tarek A. Salama. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.021

H.A. Soliman, T.A. Salama / Chinese Chemical Letters 24 (2013) 404–406
405
Table 1
Table 2
Optimization of the amount of tetrachlorosilane.
[
TCS-catalyzed synthesis of 1,8-dioxo-octahydroxanthenes.
O
Entry Substrate
Time (h) Product Yield (%)a
O
Ph
O
O
SiCl , ClCH CH Cl
4
2
2
1
2
3
4
5
6
7
8
9
10
Benzaldehyde
3
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
95
94
93
95
85
92
90
91
–
+
Ph-CHO
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
4-Nitrobenzaldehyde
2.5
2
o
3 h, 60-70 C
O
3
2.5
2
Entry
SiCl4 (mol %)
Yield (%)a
3,4,5-Trimethoxybenzadehyde
4-Hydroxy-3-methoxybenzaldehyde
4-Cyanobenzaldehyde
2
3
1
2
3
4
5
0
10
15
20
30
0
59
78
90
90
3
n-Butyraldehyde
3
-
a
Isolated yield
a
Isolated yield.
convenient to conduct the reaction at 60–70 8C, which shortened
the reaction time to 2–3 h.
The reaction of dimedone with aryl aldehydes in the presence of
SiCl4 works well giving excellent yields of the respective 1,8-dioxo-
octahydroxanthene (Scheme 1 and Table 2).
Synthesis of aryl-pyrano[3,2-c]tetrazolo[1,5-a]azepine deriva-
tives: A typical procedure for the reaction of 3 with SiCl4/NaN3
in the ratio 1:2:6, to give 4. To a mixture of 3 and NaN3 in CH3CN at
room temperature, SiCl4 was added and the mixture warmed at
60–70 8C with stirring until TLC showed the disappearance of the
starting material. The reaction was then poured into aq. NaHCO3
solution and the mixture was extracted with EtOAc. The extract
were dried over MgSO4 and concentrated, then cooled to give pure
4.
The general process was examined by applying the reaction
conditions to various substituted aromatic aldehydes bearing
either, electron-withdrawing groups (such as nitro, cyano, halide),
or electron donating groups (such as methyl, hydroxyl, mono- or
tri-methoxy groups). In all cases studied, the respective 1,8-dioxo-
octahydroxanthenes were obtained in excellent isolated yields
without chromatography. However, the reaction failed with
aliphatic aldehydes. For example, the reaction with n-butyralde-
hyde gave a complex mixture with no preparative value (entry 10,
Table 1). The structures of isolated 1,8-dioxo-octahydroxanthene
derivatives were assigned based on their spectral analyses as well
as by matching their melting points with reported analogues [7].
The mechanism of synthesis of xanthene derivatives 3 has been
proposed through a SiCl4-catalyzed manner, resembling the well-
documented Lewis acid-catalyzed cascade Knovenagel condensa-
tion–Michael addition and cyclo-dehydration sequence [7(f) and
(g)].
Due to the important biological activities of pyran moieties [24]
as well as the existence of some potential drugs related to the
terazolo[1,5-a]azepine core structure (e.g. pentetrazol) [25], we
thought it may be useful to construct a chemical skeleton including
both these moieties. From this point of view, and aiming at
exploring the synthetic utility of the prepared 1,8-dioxo-octahy-
droxanthenes at the same time, we pursued studying their reaction
with silyl azides (in situ formed by reaction of TCS and NaN3)
envisaging the formation of novel tetrazoloazepine derivatives.
According to the well-documented procedure [20–23], the
reaction of 1,8-dioxo-octahydroxanthenes with TCS–NaN3 led to
Data for 4b,d as representative examples are showed. 4b:
Mp > 300 8C; IR (KBr, cmꢀ1):
n
2964, 2934, 2836, 1652, 1607, 1510,
1461, 1420, 1362, 1329, 1203, 1157, 837, 770, 585; 1H NMR
(300 MHz, DMSO-d6): 7.34 (d, 2H, J = 8.5 Hz, Ar-H), 6.78 (d, 2H,
d
J = 8.5 Hz, Ar-H), 5.59 (s, 1H, CH), 3.65 (s, 3H, OCH3), 4.44 (s, 4H,
2 ꢁ N–CH2), 2.81 (s, 4H, 2 ꢁ CH2), 1.03 (s, 6H, 2 ꢁ CH3), 0.94 (s, 6H,
2 ꢁ CH3); EI-MS: 460 (M+); Anal. Calcd. for C24H28N8O2 (460.23): C
62.59, H 6.13, N 24.33. Found: C 62.42, H 6.07, N 24.19. 4d:
Mp > 300 8C; IR (KBr, cmꢀ1):
1402, 1329, 1177, 1116, 832, 711, 609; 1H NMR (300 MHz, DMSO-
d6): 7.46 (d, 2H, J = 6 Hz, Ar-H), 7.31 (d, 2H, J = 6 Hz, Ar-H), 5.63 (s,
n 2964, 2934, 2874, 1652, 1514, 1485,
d
1H, CH), 4.46 (q, 4H, J = 12 Hz, 2 ꢁ N–CH2), 2.83 (br s, 4H, 2 ꢁ CH2),
1.04 (s, 6H, 2 ꢁ CH3), 0.92 (s, 6H, 2 ꢁ CH3); EI-MS: 464 (M+); Anal.
Calcd. for C23H25ClN8O (464.18): C 59.41, H 5.42, N 24.10. Found: C
59.30, H 5.27, N, 23.95.
3. Results and discussion
The reaction between dimedone (1, 2 mol) and benzaldehyde
(2a, 1 mol) in the presence of SiCl4 was studied as a model reaction.
An optimization study of the reaction conditions has shown that
only 20 mol% of SiCl4 was sufficient to achieve the highest yields in
dichloroethane as the solvent (Table 1). However, the reaction can
proceed at room temperature over a long time, but it was more
a
smooth formation of novel functionalized pyrano-bis[3,2-
c]tetrazolo[1,5-a]azepines in very good yields (Scheme 2 and
Table 3).
The structural elucidation of tetrazoloazepines 4 was assigned
on the basis of both elemental and spectral analyses. In the IR
spectra, no absorption for the carbonyl group (C55O) was observed,
rather, the products displayed the characteristic C55N stretching
[(Schme_1)TD$FIG]
2
R
3
1
R
R
O
H
O
SiCl , ClCH CH Cl
O
O
4
2
2
+
o
Table 3
60-70 C
1
3
O
R
R
TCS–NaN3 mediated syntheis of aryl-pyrano-bis-tetrazoloazepine derivatives.
2
R
O
3a-i
1
2a-i
Entry
R
R0
Time (h)
Product
Yield (%)a
1
3
2
1
2
3
2f, 3f: R = R = H, R = NO
2a, 3a: R = R = R = H
2
1
2
3
4
5
6
H
H
3
2
2
3
3
3
4a
4b
4c
4d
4e
4f
82
85
87
84
83
78
1
2
3
1
3
2
2g, 3g: R = R = R = OMe
2b, 3b: R = R = H, R = Cl
OMe
Br
H
1
2
3
1
3
2
H
2h, 3h: R = OMe, R = OH, R = H
2c, 3c: R = R = H, R = Br
1
3
2
1
3
2
Cl
H
2i, 3i: R = R = H, R = CN
2d, 3d: R = R = H, R = Me
CN
OH
H
1
3
2
2e, 3e: R = R = H, R = OMe
Scheme 1. Synthesis of 1,8-dioxo-octahydroxanthenes.
OMe
a
Isolated yield.

[
H.A. Soliman, T.A. Salama / Chinese Chemical Letters 24 (2013) 404–406
R
R
R'
O
R'
4a: R = R' =H
N
N
N
N
O
4b: R = OMe, R' = H
4c: R = Br, R' = H
4d: R = Cl, R' = H
4e: R = CN, R' = H
4f: R = OH, R' = OMe
N
N
SiCl -NaN
4
3
N
N
o
MeCN, 60-70 C
O
O
3
4a-f
Scheme 2. Synthesis of aryl-pyrano-bis-tetrazoloazepine derivatives.
band at n
max 1652 cmꢀ1, supporting the formation of bis-tetrazole.
(e) T.S. Jin, J.S. Zang, A.Q. Wang, et al., Ultrasound-assisted synthesis of 1,8-dioxo-
octahydroxanthene derivatives catalyzed by p-dodocylbenzenesulfonic acid in aque-
ous media, Ultrason. Sonochem. 13 (2006) 220–224;
(f) A. Llangovan, S. Malayappasamy, S. Mularidharan, et al., A highly efficient green
synthesis of 1,8-dioxo-octahydroxanthenes, Chem. Central J. 5 (2011) 81, http://
dx.doi.org/10.1186/1752-153X-5-81 and references cited therein;
(g) S. Kantevari, R. Bantu, L. Nagarapu, HClO4–SiO2 and PPA–SiO2 catalyzed efficient
one-pot Knoevenagel condensation, Micheal addition and cyclodehydration of dime-
done and aldehydes in acetonitrile, aqueous and solvent free condition: scope and
limitations, J. Mol. Catal. A: Chem. 269 (2007) 53–57.
The 1H NMR spectra of bis-tetrazoloazepines were in agreement
with the depicted structures. For example, the 1H NMR spectra of
4b showed a singlet at
and two characteristic singlets corresponding to four protons each,
by intergration, at 4.44 and 2.81. These two singlets are most
d 5.59 attributed to the methine proton (CH)
d
likely attributed to the protons at the carbon attached to the
nitrogen (2 ꢁ N–CH2) and allylic protons (2 ꢁ CH2–C55C), respec-
tively. Furthermore, mass spectrum of 4b displayed the m/z 460
peak corresponding in mass to its molecular ion (M+). The
simplicity, mild conditions, cheap, ease of reagent handling and
toleration to diverse substrates are features of the present
synthetic procedure.
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4. Conclusion
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cyclooxygenase-2 (COX-2) inhibitors, Bioorg. Med. Chem. Lett. 22 (2012) 2235–
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thesis: mild and efficient one-pot syntheses of E-3-benzylideneflavanones, cou-
marin-3-carbonitriles/carboxamides, and benzannulated spiropyran derivatives,
ARKIVOC ix (2012) 242–253.
[15] T.A. Salama, Z. Novak, N-Halosuccinimide/SiCl4 as mild and efficient systems for
the a-mono-halogenation of carbonyl compounds and for benzylic halogenation,
Tetrahedron Lett. 52 (2011) 4026–4029.
[16] T.A. Salama, A.S. El-Ahl, S.S. Elmorsy, et al., A new convenient procedure for the
thionation of carbonyl compounds utilizing tetrachlorosilane-sodium sulfide,
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and efficient one-pot, three-component synthesis of b-amido ketone libraries,
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In conclusion, a new, highly efficient approach to 1,8-dioxo-
octahydroxanthenes catalyzed by TCS has been presented. The
mild reaction conditions of the protocol, inexpensive reagents and
ease of handling, the simple purification of products by recrystal-
lization are the advantages of the present method. In addition, use
of the prepared 1,8-dioxo-octahydroxanthenes in synthesis of
novel aryl-pyrano-di-[3,2-c]tetrazolo[1,5-a]azepine derivatives by
readily available TCS–NaN3 was also presented. The novel,
functionalized pyrano-bistetrazoloazepines described in this work
may find additional importance through biological evaluation
which is being currently undertaken.
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