Synthesis of substituted triarylpyran through an unexpected intramolecular cyclization

Article abstract of DOI:10.1080/00397910701356835

An unexpected cyclization of 1,1,2-tris-(4-methoxyphenyl)-pentan-1,5-diol (7) yielding highly substituted (±) 2,2,3-tris-(4-methoxyphenyl) tetrahydropyran (10) under mild reaction conditions is described. A reaction mechanism for the formation of this pro

Full text of DOI:10.1080/00397910701356835

Synthetic Communicationsw, 37: 2031–2037, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701356835
Synthesis of Substituted Triarylpyran
through an Unexpected Intramolecular
Cyclization
´
Atul Gupta, Gloria Beazley, Jean Lee, and Gervais Berube
Department of Chemistry and Biology, Research Group in Molecular
´
´ `
and Cellular Biopathology, University of Quebec at Trois-Rivieres,
`
Trois-Rivieres, Canada
Abstract: An unexpected cyclization of 1,1,2-tris-(4-methoxyphenyl)-pentan-1,5-diol
(7) yielding highly substituted (+) 2,2,3-tris-(4-methoxyphenyl)tetrahydropyran (10)
under mild reaction conditions is described. A reaction mechanism for the formation
of this product is postulated.
Keywords: intramolecular cyclization, triarylethylenes (TAEs), triarylpyrans, SERMs
The triarylethylenes (TAEs) 1 are members of a class of compounds showing
promising biological activity in estrogen-dependent disorders such as breast
cancer, osteoporosis, central nervous system (CNS)/cardiovascular system
(CVS), and fertility regulation.[1] Several of these compounds have been
found to be tissue selective and are referred to as selective estrogen receptor
modulators (SERMs)[2] Many derivatives possessing TAE residue or as
modified TAE such as the triarylpropenones (TAPs)[3,4] 2 and 3 have been
investigated; some of them have led to the development of drugs such as clo-
miphene 1 (R ¼ Cl) for fertility induction, tamoxifen[5] 1 (R ¼ CH2CH3) and
the related derivative tormifene 1 (R ¼ CH2CH2Cl) for breast cancer, and
Received in the USA November 7, 2006
´ ´
Address correspondence to Gervais Berube, Department of Chemistry and Biology,
´
Research Group in Molecular and Cellular Biopathology, University of Quebec
` `
at Trois-Rivieres, C.P. 500, Trois-Rivieres, Canada G9A 5H7. E-mail: gervais.
berube@uqtr.ca
2031

2032
A. Gupta et al.
Figure 1. Triarylethylenes and related SERMs derivatives.
many more candidate drugs (Fig. 1). In our continuous search for more
selective and potent chemotherapeutic agents for the treatment of estrogen-
dependent cancers such as breast, ovarian, and uterine cancers, we have pre-
viously reported some triarylethylene–platinum(II) hybrid derivatives 4 that
show good anticancer activities (Fig. 2).[6–9]
During the modification of TAE molecules designed as potential antitumor
agents, we needed to synthesize the TAE derivative, 4,5,5-tris-(4-methoxy-
phenyl)-4-penten-1-ol (9), for the preparation of estrogen-linked platinum(II)
complexes such as 4. However, instead of obtaining the desired derivative
(9), we observed an unexpected cyclization of the reaction intermediate 1,1,2-
tris-(4-methoxyphenyl)-pentan-1,5-diol (7), yielding highly substituted (+)
2,2,3-tris-(4-methoxyphenyl)-tetrahydropyran under mild reaction conditions.
This interesting reaction is reported in this article. The particularity of the
cyclic product is that it possesses two phenyl rings on a quaternary carbon
atom (2C), which is next to the oxygen heteroatom. In addition to this, there
is another phenyl ring at the neighboring carbon (3C). We noticed during the
synthesis that this cyclization reaction is reproducible and time dependent.
The synthesis of 4,5,5-tris-(4-methoxyphenyl)-4-penten-1-ol (9) was
started with desoxyanisoin 5. Alkylation of 5 with 3-tetrahydropyranyl-1-
iodopropyl ether was achieved using sodium hydride in THF to give
compound 6 in 75% yield (Scheme 1). 3-Tetrahydropyranyl-1-iodopropyl
ether was prepared by tetrahydropyranyl protection of commercially
available 3-bromopropanol followed by SN2 bromine exchange with iodine
in 95% yield. The addition of an excess of 4-methoxyphenylmagnesium

Substituted Triarylpyran
2033
Figure 2. Triethylene-based platinum(II) complexes.
bromide to ketone 6 and subsequent treatment of the crude tertiary alcohol
intermediate 1,1,2-tris-(4-methoxyphenyl)-pentan-1,5-diol (7) with pyridi-
nium-p-toluenesulfonate in ethanol at reflux produced the desired tripheny-
lethylene alcohol 9 along with the triphenylpyran derivative 10. The
Scheme 1. (a) 3-Tetrahydropyranyl-1-iodopropane NaH, THF, 258C, 17 h; (b)
4-methoxyphenylmagnesium bromide, ether, 258C, 17 h; (c) PPTs, ethanol, reflux,
20 h.

2034
A. Gupta et al.
proportion of compounds 9 and 10 vary with time; a shorter reaction time
gives mainly compound 9 and a longer reaction time gives mainly
compound 10.
It is presumed that the triphenylethylene derivative 9 comes as the result of
the dehydration of the tertiary alcohol intermediate and simultaneous deprotec-
tion of the terminal tetrahydropyranyl ether (path A, Scheme 1). On the other
hand, compound 10 comes from the cyclization of the primary alcohol on the
stabilized carbocation intermediate 8 (path B, Scheme 1). The stability of car-
bocation and the ease of the formation of six-membered rings may be the
driving force for the cyclization reaction. This explains the formation of
(+)-2,2,3-tris-(4-methoxyphenyl)tetrahydropyran 10 as the major compound
instead of the initially expected 4,5,5-tris-(4-methoxyphenyl)-4-penten-1-ol
(9) derivative.
The synthesis of oxygen heterocycles, in particular six-membered rings
with several substitutions, is often difficult because of their labile nature.
The present report adds some valuable information for the synthesis of trisub-
stituted arylpyrans under mild reaction conditions.
EXPERIMENTAL
Anhydrous reactions were performed under an inert atmosphere; the setup was
assembled and cooled under dry nitrogen. Unless otherwise noted, starting
material, reactant, and solvents were obtained commercially and were used
as such or purified and dried by standard means.[10] Organic solutions were
dried over magnesium sulphate (MgSO4) and evaporated on a rotatory evap-
orator under reduced pressure. All reactions were monitored by UV fluor-
escence, stained with iodine, or sprayed with an aqueous solution of
phosphomolybdic acid followed by heating the plate at 1358C. Commercial
thin-layer chromatography (TLC) plates were Sigma T 6145 (polyester
silica gel 60 AO, 0.25 mm). Flash chromatography was performed
according to the method of Still and co-workers on Merck grade 60 silica
gel, 230–400 mesh.[11] All solvents used in chromatography had been
distilled. The infrared (IR) spectra were taken on a Nicolet model 205 FT-
IR spectrophotometer. Mass spectral (MS, m/e) assays were obtained using
a VG Micromass 7070 HS instrument using an ionization energy of 70 eV.
Nuclear magnetic resonance (NMR) spectra were obtained in a CDCl3
solution (unless otherwise noted) on a General Electric GE 300-NB
(300 MHz) instrument; chemical shifts were measured relative to internal
standards: tetramethylsilane (TMS, d 0.0 pm) for 1H NMR and CDCl3
(d 77.0 ppm) for 13C NMR. Chemical shifts (d) are expressed in parts
per million (ppm), the coupling constants (J ) are expressed in Hertz (Hz).
Multiplicities are described by the following abbreviations: s for singlet, d
for doublet, dd for double of doublet, t for triplet, q for quartet, m for
multiplet, #m for several multiplets, and br s for broad singlet. The NMR

Substituted Triarylpyran
2035
assignments were assisted by 13C-1H correlation (HET-CORR) two-dimen-
sional spectra.
Synthesis of 1-Tetrahydropyranyloxy-3-bromopropane
A solution of 3-bromo-1-propanol (4.75 g 34 mmol), dihydropyran (3.32 g
[3.6 ml], 39.5 mmol), and pyridinium p-toluenesulfonate (PPTs, 10 mg) in
dichloromethane (50 ml) was stirred for 5 h under nitrogen. Afterward,
sodium bicarbonate (500 mg) and MgSO4 (5.0 g) were added to the
reaction mixture and stirred 15 min before being filtered on a short pad of
Celitew/silica gel (1 cm/4 cm) using dichloromethane as the eluent. The
filtrate was evaporated to a viscous oil 4 (7.62 g, 99%), which was used
without further purification in the next step. IR (neat) cm21: 1170–1000
(C-O); 1H NMR (d): 4.61 (1H, J ¼ 2.90 Hz, OCHO), 3.87, 3.52 (4H,
2 ꢀ m, CH2OCHCH2), 3.54 (2H, t, J ¼ 6.5 Hz, CH2Br), 2.10 (2H, p,
J ¼ 6.20 Hz, CH2CH2CH2), 1.40–2.00 (6H, m, THP); MS (m/e): 221
(Mþ), 120 (Mþ-OTHP).
Synthesis of 1-Tetrahydropyranyloxy-3-iodopropane
Sodium iodide (7.43 g, 49.5 mmol) was added to a solution of crude 1-tetra-
hydropyranyloxy-3-bromopropane (7.47 g. 33.5 mmol) in dry acetone
(150 ml). The reaction mixture was stirred at 258C for 5 h. After completion
of reaction, most of the solvent was evaporated, and the residue was trans-
ferred to an extraction flask with ether (100 ml) and water (100 ml). The
organic phase was washed with water (6 ꢀ 50 ml), dried, filtrated, and con-
centrated to a viscous liquid. The crude iodide 5 (8.8 g, 98%) was used as
1
such at the alkylation step. IR (neat) cm21: 1170–1000 (C-O), H NMR
(d): 4.61 (1H, t, J ¼ 3.30 Hz, OCHO), 3.83, 3.50 (4H, 2 ꢀ m,
CH2OCHCH2), 3.30 (2H, t, J ¼ 6.70 Hz, CH2I), 2.10 (2H, p, J ¼ 6.50 Hz,
CH2CH2CH2), 1.40–2.00 (6H, m, THP); MS (m/e): 269 (Mþ -H), 169
(Mþ-OTHP).
Synthesis of 1,2-Bis-(4-methoxyphenyl)-5-
tetrahydropyranyloxypentanone (6)
To a stirred suspension of sodium hydride (1.2 g. 29.8 mmol, 60% dispersion
in mineral oil) in dry tetrahydrofuran (THF, 200 ml), desoxyanisoin (5)
(6.97 g, 27.2 mmol) was rapidly added. The reaction mixture was heated
(508C) on a water bath for 1 h under a nitrogen atmosphere. After cooling,
the 1-tetrahydropyranyloxy-3-iodopropane (8.06 g, 29.8 mmol) was added
dropwise, and the resulting mixture was stirred overnight (17 h). Most of

2036
A. Gupta et al.
the solvent was then evaporated, and the residue was diluted with ether
(200 ml) and treated with water (50 ml). The ethereal phase was washed
thoroughly with water (6 ꢀ 50 ml), dried, and evaporated to give an oil,
which was purified by flash chromatography (hexane–acetone, 9:1). A
viscous oil was obtained (8.02 g, 74%). IR (neat) cm21: 1674 (C55O), 1599
1
(C55C), 1254 (C-O); H NMR (d): 7.96, 6.85 and 7.22, 6.81 (8H, two pairs
of d, J ¼ 8.87 Hz and 8.71 Hz, ArH), 4.53 (2H, m, OCHO and CH), 3.83
and 3.47 (2H, two m, CH2OTHP), 3.76 and 3.39 (2H, two m, CHOCH2),
3.80 and 3.73 (6H, two s, OCH3), 2.25–1.40 (10H, m, 5 ꢀ CH2); 13C
NMR (d): 198.52, 163.05, 158.35, 131.84, 130.82(2), 129.66, 128.09(2),
114.11(2), 113.53(2), 98.69, 67.30, 62.24, 62.11, 55.26, 55.07, 51.86, 30.61,
27.58, 25.38, 19.57; MS (m/e): 398 (M þ ), 314 (Mþ -DHP).
Synthesis of 4,5,5-Tris-(4-methoxyphenyl)-4-penten-1-ol (9) and
(+) 2,2,3-Tris-(4-methoxyphenyl)tetrahydropyran (10)
A Grignard reagent was prepared from 1.93 g (79.4 mmol) of magnesium and
12.5 g (8.36 ml, 66.8 mmol) of 4-bromoanisole in the presence of a crystal of
iodine in 100 ml of dry ether. The Grignard reagent was usually ready after
stirring at room temperature overnight (17 h), but sometimes it required
heating at reflux to initiate the reaction. A solution of ketone 6 (5.0 g,
12.6 mmol) in dry ether (300 ml) was treated with the excess of the
Grignard reagent for 3 h under nitrogen at 258C and was then hydrolyzed
with 50 ml of 10% aqueous ammonium chloride. The ethereal phase was
washed with water (5 ꢀ 50 ml), dried, and evaporated to give the crude
tertiary alcohol intermediate 7. The oily residue was dehydrated and depro-
tected in 150 ml of 95% ethanol in the presence of PPTs (100 mg,
0.34 mmol) at reflux for 20 h. After evaporation of the solvent, the residue
was taken with ether and extracted with water (5 ꢀ 50 ml), dried, and evapor-
ated to an oil. Flash chromatography (hexane–acetone, 85:15) gave 9 and 10
in 6% and 85% yield as viscous oils. Note: A shorter reaction time (i.e., 4.5 h)
would result in the formation of 1and 2 in equivalent proportion.
Spectral Data of 4,5,5-Tris(4-methoxyphenyl)-4-penten-1-ol (9)
1
IR (neat) cm21: 3640–3150 (OH), 1605 (C55C), 1242 (C-O); H NMR (d):
7.13, 6.85 and 7.02, 6.68 and 6.79, 6.54 (12H three pairs of d, J ¼ 8.67 Hz,
8.73 Hz, and 8.80 Hz, ArH), 3.75, 3.68 and 3.62 (9H, 3 ꢀ s, OCH3), 3.43
(2H, t, J ¼ 6.63 Hz, CH2OH), 2.47 (2H, m, C55CCH2), 2.01 (1H, br s, OH),
1.56 (2H, m, CH2CH2CH2); 13C NMR (d): 157.95, 157.53, 157.11, 138.12,
137.89, 136.09, 135.66, 134.46, 131.68(2), 130.45(2), 130.35(2), 113.32(2),
113.17(2), 112.56(2), 62.45, 54.95, 54.82, 54.75, 31.94 (2); MS (m/e): 404
(Mþ, 100%), 386 (Mþ - H2O, 3.4%), 359 (Mþ - C2H4OH, 30.2%).

Substituted Triarylpyran
2037
Spectral data of (+) 2,2,3-Tris(4-methoxyphenyl)-
tetrahydropyran (10)
IR (neat) cm21: 1242 (C-O), 1H NMR (d): 7.42, 6.86 and 7.31, 6.65 and 7.19,
6.57 (12H, three pairs of d, J ¼ 8.88 Hz, 8.77 Hz and 8.90 Hz, 3 ꢀ ArH), 4.00
(1H, t, J ¼ 3.85 Hz, CH), 3.96 (1H, m, CHHO), 3.75 (1H, m, CHHO), 3.77,
3.70 and 3.62 (9H, 3 ꢀ s, OCH1), 2.25, 1.94, 1.76 and 1.27 (4H, 4 ꢀ m,
CH2CH2CH2O); 13C NMR (d): 157.88, 157.08, 156.81, 139.52, 137.37,
134.89, 131.17(2), 127.89(2), 126.34(2), 113.76(2), 112.84(2), 112.65(2),
81.26, 62.54, 55.15, 54.91(2), 44.14, 27.58, 20.61; MS (m/e): 404 (Mþ,
24.3%), 386 (Mþ - H2O, 2.2%), 359 (Mþ -C2H4OH, 6.7%).
ACKNOWLEDGMENTS
We are grateful to the Fonds de Recherche sur la Nature et les Technologies du
´
Quebec (FQRNT) for generous financial support.
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