A simple route for the synthesis of 3,3,3′,3′-tetramethyl-2,3, 3′,4′-tetrahydro-1H,1′H-[4,9′-bixanthene]-1, 1′(2′H,9′H)-dione and its derivatives catalyzed by Mn 2+ and other transition metal cations

Article abstract of DOI:10.1016/j.tetlet.2012.05.116

A simple and efficient unusual coupling reaction of 9-(2-hydroxy-4,4- dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1- one and its derivatives was accomplished in the presence of Mn²⁺, Cu²⁺, Cd²⁺

Full text of DOI:10.1016/j.tetlet.2012.05.116

Tetrahedron Letters 53 (2012) 4096–4099
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple route for the synthesis of
3,3,30,30-tetramethyl-2,3,30,40-tetrahydro-1H,10H-[4,90-bixanthene]-1,10(20H,90H)-
dione and its derivatives catalyzed by Mn2+ and other transition metal cations
Nader Noroozi Pesyan a, , Vali Golsanamloo a, Shahnaz Ganbari a, Ertan Sßahin b
⇑
a Department of Chemistry, Faculty of Science, Urmia University, 57159 Urmia, Iran
b Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2012
Revised 5 May 2012
Accepted 24 May 2012
Available online 30 May 2012
A simple and efficient unusual coupling reaction of 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-
yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one and its derivatives was accomplished in the pres-
ence of Mn2+, Cu2+, Cd2+, Hg2+, Fe3, or La3+. The structure elucidation was accomplished by IR, 1H NMR, 13
NMR, X-ray crystallography, UV–Visible and elemental analysis. A reaction mechanism is proposed.
C
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Coupling reaction
Metal cation
Dimedone
[4,90-Bixanthene]-1,10(20H,90H)-dione
R1
Organic molecules containingxanthene moieties are of biological
importance and are useful in drug discovery.1 The xanthene
derivative, (9S)-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-
1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one is a selec-
tive and orally active neuropeptide Y Y5 receptor antagonist.1b–d
Chromenes are an important class of compounds, and are often
found as the maincomponents ofmany naturally occurringproducts
employed as cosmetics, pigments, and as potential biodegradable
agrochemicals.1e–i Some xanthene derivatives demonstrate photo-
activated insecticidal and pest-control activity,1j,1k and anticancer
properties.11
Xanthenes are also very efficient laser dyes and show outstand-
ing photophysical properties.2 For example, the aggregation
phenomena of xanthene dyes has been reviewed,2d as has their
photochemistry,2e electron transfer,2f triplet absorption spectra,2g
and photodegradation.2h For the fluoresceins in particular, the
spectral properties and photochemistry have been reviewed,2i the
photochemistry of rhodamines has been investigated2j as has
hydrogen generation during the photolysis of water.2k There have
been many new uses for xanthenes reported. These include as
nonlinearoptical (NLO) materials,3a charge control agents in electro-
photographic toners (laser printers and photocopiers),3b and as
markers or biological stains.3c Rhodamines and rosamines, in
particular, have been used in inks for ink-jet printers. There has also
O
R2
O
R1
R3
R2
O
O
O
HO
R1
O
O
R3
M
2
2
EtOH,
reflux
R2
O
O
O
R3
1
R3
R1
R1 = R2 = R3 = H ( )
a
O
R1 + R2 = C4H4, R3 = H (b)
R1 = R2 = H, R3 = OMe (c)
R1 = R3 = H, R2 = Br (d)
R1 = R3 = H, R2 = NO2 (e)
R2
M
R2
O
R1
M: MnCl2.4H2O, CuCl2.2H2O,
Cd(NO3)2.4H2O, HgCl2,
Ni(NO3)2.6H2O, ZrCl4,
R3
O
O
O
FeCl3.6H2O, LaCl3.7H2O,
Zn(NO3)2.6H2O, AgNO3
3
⇑
Corresponding author.
E-mail address: n.noroozi@urmia.ac.ir (N. Noroozi Pesyan).
Scheme 1. Coupling reaction of 1 in the presence of various metal cations giving 2.
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.116

N. Noroozi Pesyan et al. / Tetrahedron Letters 53 (2012) 4096–4099
4097
R1
R3
However, this reaction was unsuccessful in the presence of all
these mentioned transition metal cations. The unusual coupling
reaction of 1a–e in the presence of MnCl2ꢀ4H2O, CuCl2ꢀ2H2O,
Cd(NO3)2ꢀ4H2O, HgCl2 FeCl3ꢀ6H2O, and LaCl3ꢀ7H2O afforded dimers
2a–e in good yields (Scheme 1 and Table 1).
R2
CHO
OH
AcOH
reflux
+
HO
R1
O
O
O
O
In the IR spectrum of 2a, the hydroxy frequency disappeared in
comparison with that of 1a at 3181 cmꢁ1. The 1H NMR spectrum of
2a showed three singlets for the four methyl protons at d 0.95, 1.11,
and 1.48, a singlet for the aliphatic C–H proton at d 4.85 and a mul-
tiplet for the diastereotopic methylene protons in the range d 2.29–
2.64. In the aromatic region, a triplet at d 6.87 (1H), two multiplets
at d 6.94–6.98 (3H) and at d 7.05–7.10 (3H), and a triplet at d 7.20
were also shown. The 13C NMR spectrum of 2a showed thirty dis-
tinct peaks. The UV–visible spectrum of 2a demonstrated absorp-
tion maxima at 469 nm in ethanol. These data confirmed the
structure of 2a. We performed these reactions in the presence of
FeCl3ꢀ6H2O and LaCl3ꢀ7H2O under the same conditions but the reac-
tion yield was low. No products 2a–2e were obtained in the pres-
ence of Ni(NO3)2ꢀ6H2O, Zn(NO3)2ꢀ6H2O, ZrCl4, or AgNO3 under the
same conditions. No explanation can be offered for this outcome.
We also performed the coupling reaction of ligands 1b–1e in the
presence of the above mentioned cations under the same condi-
tions giving compounds 2b–2e (Scheme 1 and Table 1).
R2
4
5
R1 = R2 = R3 = H ( )
a
R1 + R2 = C4H4, R3 = H (
)
O
b
R3
R
R
1 = R2 = H, R3 = OMe ( )
c
1 = R3 = H, R2 = Br (d)
1
R1 = R3 = H, R2 = NO2 (e)
Scheme 2. Reaction of dimedone (4) with salicylaldehyde (5a) and its derivatives
5b–5e.
been a significant amount of activity on the use of xanthenes, and in
particular rhodamines, as laser dyes.3d
As part of our ongoing studies on the synthesis of dimeric
xanthene derivatives, herein we report the unusual coupling
of 4-(3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-5-
hydroxycyclohex-4-ene-1,3-dione (1a) and its derivatives 1b–e in
the presence of various transition metal cations (Scheme 1).4
Our initial aim was to attempt the synthesis of a metal complex
3 via the reaction of 1 with transition metal cations originating from
MnCl2ꢀ4H2O, CuCl2ꢀ2H2O, Cd(NO3)2ꢀ4H2O, HgCl2, Ni(NO3)2ꢀ6H2O,
ZrCl4, FeCl3ꢀ6H2O, LaCl3ꢀ7H2O, Zn(NO3)2ꢀ6H2O, or AgNO3.
Compounds 1a–1e were synthesized based on the literature
procedures5 by the reaction of dimedone (4) with salicylaldehyde
(5a), 2-hydroxy-1-naphthaldehyde (5b), 2-hydroxy-3-methoxy-
benzaldehyde (5c), 2-hydroxy-5-bromobenzaldehyde (5d), and
H
O
O
O
O
O
O
M
2
O
+
O
O
M
O
O
A
6
O
O
O
H
O
O
3a
O
O
O
O
O
B[I]
O
O
B[II]
O
+ H
O
O
O
O
A
O
O
- H
O
H
O
O
O
2a
C
Scheme 3. Proposed mechanism for the formation of 2a.

4098
N. Noroozi Pesyan et al. / Tetrahedron Letters 53 (2012) 4096–4099
Table 1
Reactions of 1a–1e with various metal cations
Entry
Metal salt
Yield (%)
2a
2b
2c
2d
2e
1
2
3
4
5
6
7
8
9
10
MnCl2ꢀ4H2O
CuCl2ꢀ2H2O
Cd(NO3)2ꢀ4H2O
HgCl2
60a
50
50
45
55
45
45
40
—
75
60
60
50
—
60
45
40
45
—
40
30
30
35
—
b
Ni(NO3)2ꢀ6H2O
—
—
b
ZrCl4
—
—
—
—
FeCl3ꢀ6H2O
LaCl3.7H2O
Zn(NO3)2ꢀ6H2O
AgNO3
35
30
30
25
—
30
35
—
35
30
—
30
30
—
b
—
—
b
—
—
—
—
a
Isolated yield.
No reaction.
b
Table 2
UV–visible data of 2a–2e in ethanol
Compound
kmax
Logemax
2a
2b
2c
2d
2e
243, 288, 443
244, 285, 488
242, 279, 464
244, 282, 451
244, 284, 335, 398
3.074, 2.994, 0.771
2.639, 2.642, 1.130
2.648, 2.664, 0.617
2.730, 2.832, 1.747
2.704, 2.769, 2.771, 2.433
Figure 1. UV–visible spectra of 1a–1e and 2a–2e in ethanol.
2-hydroxy-5-nitrobenzaldehyde (5d) in acetic acid under reflux
(Scheme 2).
The proposed reaction mechanism for the formation of 2a is
shown in Scheme 3. It seems that after formation of complex 3a,
it cleaved to intermediates 6 and A. Then the Michael addition of
A with the b-position of other A affords intermediate B. This inter-
mediate (B) can exist in two mesomeric forms B[I] and B[II]. The
proton capture of these forms affords intermediate C. Finally, inter-
mediate C converts into 2a by loss of a proton. In Scheme 3, the
nucleophilic attack of fragment A was enforced by the lone pair
on the oxygen atom. There is some evidence that the bis-dimedone
derivative fragmented into two parts on attack of a nucleophilic
carbon on a methine carbon.6 All attempts to isolate and character-
ize 6 failed.
Figure 2. ORTEP drawing of the molecule 2a. Thermal ellipsoids are shown at 30%
probability level.
X-ray diffraction analysis of 2a was undertaken.7 The results
of this study confirmed unambiguously the proposed structure
(Fig. 2).
The UV–visible spectra of 1a–1e and corresponding dyes 2a–2e
are shown in Figure 1. The kmax and corresponding logemax data are
Acknowledgment
summarized in Table 2. The kmax of ligands 1a–1e appeared in the
ultraviolet absorption region. In contrast, the corresponding prod-
ucts 2a–2e absorbed in both the ultraviolet and visible regions.
We thank the Urmia University Research Council for financial
support of this work.
Obviously, in dye 2b the p?
p⁄ (K-band) undergoes a small batho-
chromic shift due to expansion of the conjugated system involving
the naphthyl. In 2e, this band was hypsochromically shifted due to
the electron-withdrawing nitro group on the phenyl rings. The
presence of methoxy and bromine substituents on the phenyl rings
in 2c and 2d, respectively, caused a bathochromic shift with re-
spect to 2a and 2e (Fig. 1 and Table 2).
Supplementary data
Supplementary data (full characterization of compounds 1a–1e,
2a–2e and full crystallographic data of 2a) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.05.116.

N. Noroozi Pesyan et al. / Tetrahedron Letters 53 (2012) 4096–4099
4099
as solvent. The crude red reaction mixture was purified by preparative thin-
layer chromatography (silica gel type 60F254). After separation, the solution
was dried over MgSO4 and filtered. Finally, an orange crystalline solid was
obtained (0.075 g, 60%). A single crystal of 2a was obtained by slow evaporation
from EtOH at room temperature. Orange crystalline solid; mp 184–185 °C; FT-IR
References and notes
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Gomori, A.; Ishihara, A.; Kanatani, A.; Fukami, T. J. Med. Chem. 2008, 51, 4765–
4770; (c) Sato, N.; Ando, M.; Ishikawa, S.; Jitsuoka, M.; Nagai, K.; Takahashi, H.;
Sakuraba, A.; Tsuge, H.; Kitazawa, H.; Iwaasa, H.; Mashiko, S.; Gomori, A.;
Moriya, R.; Fujino, N.; Ohe, T.; Ishihara, A.; Kanatani, A.; Fukami, T. J. Med. Chem.
2009, 52, 3385–3396; (d) Kanatani, A.; Ishihara, A.; Iwaasa, H.; Nakamura, K.;
Okamoto, O.; Hidaka, M.; Ito, J.; Fukuroda, T.; MacNeil, D. J.; Van der Ploeg, L. H.
T.; Ishii, Y.; Okabe, T.; Fukami, T.; Ihara, M. Biochem. Biophys. Res. Commun. 2000,
272, 169–173; (e) Morinaka, Y.; Takahashi, K. Jpn. Patent 52017498, 1977 (Chem
Abstr. 1977, 87, 102299).; (f) Witte, E.C.; Neuert, P.; Roesch, A. Ger. Patent DE
3427985, 1986 (Chem. Abstr. 1986, 104, 224915).; (g) Hafez, E. A.; Elnagdi, M. H.;
Elagamey, A. A.; El-Taweel, F. A. Heterocycles 1987, 26, 903–907; (h) Li, Y.-L.;
Wang, X.-S.; Shi, D.-Q.; Tu, S.-J.; Zhang, Y. Acta Cryst. 2004, E60, o1439–o1441; (i)
Lian, C.; Lu, P.; Zhu, Y. Acta Cryst. 2009, E65, o2448; (j) Heitz, J. R. ACS Symp. Ser.
1995, 616, 1–16; (k) Heitz, J. R. In Insecticide Mode of Action; Coats, J. R., Ed.;
Academic Press: New York, 1982; pp 429–457; (l) Sweet, D.V. Registry of Toxic
Effects of Chemical Substances, 1986 ed., U.S. Dept. of Health and Human
Services, National Institute for Occupational Safety and Health, Cincinnati, Ohio.
Pleiades publishing.
2. (a) Gordon, P. F.; Gregory, P. In Critical Reports of Applied Chemistry; Griffithts,
Ed.; Blackwell: Oxford, 1984; Vol 7, pp 81–85; (b) Reisfeld, R.; Brusilovsky, D.;
Eyal, M.; Miron, E.; Burstein, Z.; Ivri, J. Chem. Phys. Lett. 1989, 160, 43–44; (c)
Zollinger, H. Color Chemistry; New York, Basel-Cambridge: Weinheim, 1991. p
349; (d) Valdes-Aguilera, O.; Neckers, D. C. Acc. Chem. Res. 1989, 22, 171–177; (e)
Valdes-Aguilera, O.; Neckers, D. C. Adv. Photochem. 1993, 18, 315–394; (f)
Chibisov, A. K.; Zakharova, G. V. Usp. Nauchn. Fotogr. 1989, 25, 114–136; (g)
Carmichael, I.; Hug, G. L. J. Phys. Chem. 1986, 15, 1–250; (h) Marchant, Y. Y. ACS
Symp. Ser. 1987, 339, 168–175; (i) Neckers, D. C. J. Photochem. Photobiol., A 1989,
471, 1–29; (j) Lopez, A. F.; Lopez, A. T.; Gil, L. E.; Lopez, A. I. Appl. Fluoresc.
Technol. 1990, 2, 8–12; (k) Le, T. H.; Akhtar, M. S.; Park, D. M.; Lee, J. C.; Yang, O-B
Appl. Catal. B: Environ. 2012, 111–112, 397–401.
(KBr): 3049, 2955, 2930, 1637, 1582, 1389, 1236, 1179, 766 cmꢁ1 1H NMR
;
(CDCl3, 300 MHz) d 7.20 (t, 2H, J = 6.6 Hz), 7.05–7.10 (m, 3H), 6.94–6.98 (m, 3H),
6.87 (t, 1H, J = 6.6 Hz), 4.85 (s, 1H), 2.29–2.64 (m, 6H), 1.48 (s, 6H), 1.11 (s, 3H),
0.95 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 197.2, 197.0, 165.9, 155.3, 150.5, 146.3,
131.9, 129.5, 129.0, 127.4, 124.7, 124.5, 124.3, 122.7, 119.9, 115.9, 114.7, 111.2,
76.6, 54.9, 53.4, 51.2, 42.2, 35.5, 32.0, 29.5, 29.3, 27.9, 27.8, 26.9; Elemental
analysis calcd (%) for C30H28O4 (452.55): C 79.54, H 6.19; found (%): C 79.56, H
6.56; UV data (EtOH): kmax, (logemax)= 243, 288, 443 nm, (3.074, 2.994, 0.771).
5. (a) Wang, X.-S.; Shi, D.-Q.; Li, Y.-L.; Chen, H.; Wei, X.-Y.; Zong, Z.-M. Synth.
Commun. 2005, 35, 97–104; (b) Zhang, P.; Yu, Y.-D.; Zhang, Z.-H. Synth. Commun.
2008, 38, 4474–4479.
6. Gheath, A. H.; Al-Orffi, N. M. J. Science and Its Applications (Garyounis
University Press) 2008, 2, 60–68.
7. For the crystal structure determination, a single-crystal of compound 2a was
used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer
(equipped with a two-dimensional area IP detector). Graphite-monochromated
MoKa radiation (k = 0.71073 Å) and oscillation scans technique with Dx = 5ꢀfor
one image were used for data collection. The lattice parameters were
determined by the least-squares methods on the basis of all reflections with
F2 > 2 (F2). Integration of the intensities, correction for Lorentz and polarization
r
effects and cell refinement was performed using CrystalClear (Rigaku/MSC Inc.,
2005) software.8 The structures were solved by direct methods using SHELXS-
979 and refined by a full-matrix least-squares procedure using the program
SHELXL-97.9 H atoms were positioned geometrically and refined using a riding
model. The final difference Fourier maps showed no peaks of chemical
significance. Crystal data for 2a:
triclinic, P-1; (no:2); unit cell dimensions: a = 9.4434(2), b = 10.0078(2),
c = 14.2287(4) Å, = 70.47(3), b = 85.76(2), = 70.1983)°; volume: 1191.2(2)
Å3; Z = 2; calculated density: 1.262 g/cm3; absorption coefficient: 0.083 mmꢁ1
C30H28O4, crystal system, space group:
a
c
;
F(000): 480; h-range for data collection 2.3–26.5°; refinement method: full-
matrix least-square on F2; data/parameters: 4882/311; goodness-of-fit on F2:
3. (a) Speiser, S.; Chisena, F. L. Spec. Publ. Roy. Soc. Chem. 1989, 69, 211–216; (b)
Nakayama, N.; Asahina, Y.; Aoki, M.; Fushimi, H.; Makita, K. (to Ricoh Co.), US
Patent, 4,933,250 (12, Jun., 1990).; (c) Torneiro, M.; Still, W. C. J. Am. Chem. Soc.
1995, 117, 5887–5888; (d) Hammond, P. R.; Feeman, J. F. U.S. Patent, 5,111,472
(May 5, 1992).
1.012; final R-indices [I > 2r(I)]: R1 = 0.079, wR2 = 0.191; R-indices (all data):
R1 = 0.189, wR2 = 0.283; largest diff. peak and hole: 0.205 and ꢁ0.224e Åꢁ3
;
Crystallographic data that were deposited in CSD under CCDC registration
number 848935 contain the supplementary crystallographic data for this Letter.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif and are available
free of charge upon request to CCDC, 12 Union Road, Cambridge, UK (fax: +44
1223 336033, e-mail: deposit@ccdc.cam.ac.uk).
4. General procedure. Preparation of 3,3,30,30-Tetramethyl-2,3,30,40-tetrahydro-
1H,10H-[4,90-bixanthene]-1,10(20H,90H)-dione (2a). In a 25 mL round bottomed
flask a mixture of 1a (0.10 g, 0.27 mmol) and MnCl2.4H2O (0.05 g, 0.27 mmol)
was dissolved in EtOH (10 mL) and was refluxed for 96 h. After a few minutes
the solution became orange then red. The reaction progress was monitored by
thin layer chromatography (TLC) using a mixture of EtOAc: n-hexane (2:1/v:v)
8. Rigaku/MSC, Inc.: 9009 new Trails Drive, The Woodlands, TX 77381.
9. Sheldrick, G. M. SHELXS97 and SHELXL97; University of Göttingen: Germany, 1997.