Solution-phase synthesis of diaryl selenides using polymer-supported borohydride.

Article abstract of DOI:10.1021/ol0058184

[reaction: see text] A new series of selenium-containing diaryl retinoids have been prepared by a new direct nickel(II)-catalyzed coupling of a diselenide with an iodoaryl in the presence of polymer-supported borohydride.

Full text of DOI:10.1021/ol0058184

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1705-1708
Solution-Phase Synthesis of Diaryl
Selenides Using Polymer-Supported
Borohydride
Corinne Millois and Philippe Diaz*
GALDERMA R&D, 635 route des Lucioles BP87, F06902
Sophia-Antipolis Cedex, France
philippe.diaz@galderma.com
Received March 15, 2000
ABSTRACT
A new series of selenium-containing diaryl retinoids have been prepared by a new direct nickel(II)-catalyzed coupling of a diselenide with an
iodoaryl in the presence of polymer-supported borohydride.
Retinoids (Figure 1), synthetic1 and natural analogues of all-
trans or 9-cis-retinoic acid, exert profound effects on cell
differentiation and proliferation.2 These biological properties
are indicative of a high potential for the treatment of
hyperproliferative disorders such as psoriasis or cancer. Many
of their biological effects are mediated by activation of
nuclear receptors. There are two known types of retinoic acid
receptors, RAR (R, â, and γ)3 and RXR (R, â, and γ),4
located in the cell nucleus. In the presence of ligand, these
receptors form dimers which bind to DNA through distinct
response elements.
reported the synthesis of a new series of selenium-containing
retinoids7 (CD3386) with potent RAR affinities. In regard
to the similarities between sulfur and selenium (structural,
potentially oxidable ...), we decided to synthesize a new series
of diarylselenium-containing RXR compounds.
A variety of synthetic routes to unsymmetrical diaryl
selenides have been described.8 Among them, the nickel-
(II)-catalyzed substitution of aryl halides by aryl selenolates9
is compatible with many functional groups. The method used
requires previous preparation of the anion from the corre-
sponding diselenide using sodium borohydride. We were
troubled with the foul smell of byproducts and by the rapid
conversion of the anion to the corresponding diselenide in
the presence of air. On the other hand, it has been shown
Others5 and us6 were interested in the synthesis of RXRs
selective diaryl sulfide compounds (CD2809). Recently we
(1) (a) Charpentier, B.; Bernardon, J. M.; Eustache, J.; Millois, C.; Martin,
C.; Michel, S; Shroot, B. J. Med. Chem. 1995, 38, 4993-5006. (b) Diaz,
P.; Michel, S.; Stella, L.; Charpentier, B. Bioorg. Med. Chem. Lett. 1997,
7, 2289-2294. (c) Diaz, P.; Gendre, F.; Stella, L.; Charpentier, B.
Tetrahedron 1998, 54, 4579-4590.
(5) Beard R. L.; Colon D. F.; Song T. K.; Davies P. J. A.; Kochhar D.
M.; Chandraratna R. A. S., J. Med. Chem. 1996, 39, 3556-1563.
(6) Bernardon J. M., C.I.R.D. GALDERMA, EP 0679630-A1, 1995;
Chem. Abstr. 1996, 124, 145647e.
(7) Diaz, P.; Gendre, F.; Bernardon, J. M. Tetrahedron Lett. 1998, 39,
9003-9006.
(8) (a) Pierini, A. B.; Rossi, R. A. J. Org. Chem. 1979, 44, 4667-4673.
(b) Gassman, P. G.; Miura, A.; Miura, T. J. Org. Chem. 1982, 47, 951-
954. (c) Osuka, A.; Ohmasa, N.; Susuki, H., Synthesis 1982, 857-858. (d)
Sindelar, K.; Svatek, E.; Metysova, J.; Metys, J.; Provita, M. Collect. Czech.
Chem. Commun. 1969, 34, 3792-3800.
(9) Cristau, H. J.; Chabaud, B.; Labaudiniere, R.; Christol, H. Organo-
metallics 1985, 4, 657-661.
(2) Sporn, M.; Roberts, A. B.; Goodman, D. S. In The Retinoids: Biology,
Chemistry, and Medecine; Raven Press: New York, 1994.
(3) (a) Guiguere, V.; Ong, E. S.; Segui, P.; Evans, R. M. Nature 1987,
330, 624-629. (b) Brand, N.; Petkovitch, M.; Krust, A.; Chambon, P.; de
The´, H.; Marchio, A.; Tiollais, P.; Dejean, A. Nature 1988, 332, 850-853.
(c) Krust, A.; Kastner, P.; Petkovitch, M.; Zelent, A.; Chambon, P. Proc.
Natl. Acad. Sci. U.S.A. 1989, 86, 5310-5314.
(4) (a) Mangelsdorf, D.; Ong, E.; Dyck, J.; Evans, R. Nature 1990, 345,
224-229. (b) Mangelsdorf, D.; Borgmeyer, U.; Heyman, R.; Zhou, J.; Ong,
E.; Oro, A.; Kakizuka, A.; Evans, R. Genes DeV. 1992, 6, 329-344.
10.1021/ol0058184 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/23/2000

Figure 1.
that diphenyl diselenide can be readily converted to the
corresponding phenylselenolate anion by polymer-supported
borohydride.10 Therefore, we were interested in developing
a new practical methodology which avoided the preformation
of the selenolate mixing polymer-supported borohydride, the
catalyst, the iodide compound, and the diselenide compound.
This paper describes the development of this new synthesis
by direct nickel(II)-catalyzed coupling of a diselenide with
an iodoaryl in the presence of polymer-supported boro-
hydride. The effect of the catalyst was examined (Table 1).
reduced the rate of coupling. Ethanol, which is more easily
removed than butanol, gave the same yield in the case of an
aryl iodide.
Table 2. Effects of the Temperature and the Aryl Halogenide
on the Coupling Reactiona
Table 1. Effect of Catalyst on the Coupling Reactiona
a For the typical procedure for the coupling reaction, see ref 11.
The optimal procedure11,12 was used to synthesize a library
(Table 3): (bpy)2NiBr2 as catalyst; ethanol and THF (4/1) to
improve solubility, as solvent, at 65 °C during 16 h. The
resulting esters were saponified, providing the corresponding
carboxylic acids. Diselenide compounds were obtained from
the action of tert-butyllithium or -magnesium followed by
selenium.13 Final products were isolated by crystallization,
which explains the variability in the yields. Coupling of ethyl
2-iodonicotinate (entries 6, 17, 21, and 37) afforded ethyl
nicotinate as the major impurity, resulting from reduction
of iodine.
a For the typical procedure for the coupling reaction, see ref 11. Methanol
was used as solvent. Temperature 60 °C.
Palladium catalyst was first assessed due to its commercial
availability, although to our knowledge there is no example
in the literature. The coupling of bis(4-chlorophenyl) di-
selenide with methyl 3-iodobenzoate and methyl 6-iodoni-
cotinate affords respectively products 1 and 2 with nickel9
or palladium catalyst. In both cases, the yields are better with
the nickel catalyst. The reactions are very clean as the
impurities are the starting materials.
The effects of temperature and halogenide were then
examined (Table 2). Bis(4-tert-butyl) diselenide was coupled
with methyl bromo- and iodobenzoate. The esters resulting
from transesterification with the alcohol used as solvent were
recovered. The lack of reactivity of the bromide compound
as compared to that with the iodide compound dramatically
(11) Typical procedure for coupling reaction: a mixture of diselenide
(0.3 mmol), iodide (0.4 mmol), catalyst (10 µmol), and resin (480 mg, 1.2
mmol) (Aldrich 32,864-2) in alcohol (4 mL) and THF (1 mL) was stirred
for 16 h at 65 °C under N2. Reaction mixture was concentrated, diluted
with water, and extracted twice with diethyl ether in cartridges (Whatman
phase separation cartridge). The organic layer was dried with Na2SO4
(sample drying device, Whatman), concentrated, purified using SPE
cartridges (Supelco, 20 mL, 5 g LC silica packing), and concentrated. Ethyl
ester of 29: mp 108 °C. ESMS m/z 432 (m + H)+.1H NMR (CDCl3) δ:
1.25 (6H, s), 1.31 (6H, s), 1.37 (3H, t, J ) 7.1 Hz), 1.69 (4H, s), 2.37 (3H,
s), 4.37 (2H, q, J ) 7.1 Hz), 6.86 (1H, d, J ) 8.3 Hz), 7.28 (1H, s), 7.65
(1H, s), 7.94 (1H, dd, J ) 8.3 Hz, J′ ) 2.2 Hz), 8.99 (1H, d, J ) 2, 2 Hz).
13C NMR (CDCl3) δ: 14.0, 22.3, 31.5, 31.6, 33.8, 34.0, 34.7, 61.0, 122.0,
122.3, 124.3, 128.6, 136.2, 136.7, 139.0, 144.1, 147.1, 150.6, 165.2, 166.1.
(10) Gibson, H.; Courtney Bailey, F. J. Chem. Soc., Chem. Commun.
1977, 815.
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Org. Lett., Vol. 2, No. 12, 2000

Table 3. Diaryl Selenides Prepared According to the Optimized Procedure11,12
Org. Lett., Vol. 2, No. 12, 2000
1707

Thiophenol and disulfide were also submitted to the same
procedure. Comparable results were obtained (Table 4).
Various interesting products were obtained in this library.
Among them, new RXR antagonists were found. Compound
29 is 10 times more potent as an RXR agonist than its sulfur
analogue.
Table 4. Diaryl Sulfides Prepared According to the Optimized
Procedure11
Acknowledgment. We thank J. M. Bernardon for his
constant interest in this program. The help of C. Raffin and
F. Gendre is also acknowledged.
1
Supporting Information Available: H NMR spectra for
compounds 3-50 and sulfur derivatives. This material is
available free of charge via Internet at http://pubs.acs.org.
OL0058184
(12) Typical procedure for saponification: the ester was stirred at 50
°C for 24 h in a 1 M solution of sodium hydroxide/EtOH-THF (1:1). The
reaction mixture was concentrated, diluted with water, acidified with HCl
1 N, and extracted with diethyl ether in cartridges (Whatman phase
separation cartridge). The organic layer was dried with Na2SO4 (sample
drying device, Whatman), concentrated, and isolated by crystallization in
heptane or heptane/CH2Cl2. 6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahy-
dronaphthalen-2-ylselanyl)nicotinic acid (29): mp 258 °C. ESMS m/z
402 (m - H)-. 1H NMR (DMSO) δ: 1.06 (6H, s), 1.11 (6H, s), 1.49 (4H,
s), 2.14 (3H, s), 6.81 (1H, d, J ) 8.3 Hz), 7.24 (1H, s), 7.45 (1H, s), 7.86
(1H, dd, J ) 8.3 Hz, J′ ) 2.2 Hz), 8.70 (1H, d, J ) 2.2 Hz), 13.12 (1H, s).
13C NMR (DMSO) δ: 22.2, 31.6, 33.8, 34.0, 34.6, 122.5, 123.4, 124.3,
128.9, 135.6, 137.7, 138.9, 143.9, 146.9, 150.7, 164.2, 166.2. IR (cm-1):
1081, 1140, 1294, 1416, 1460, 1579, 1679, 2862, 2924, 2962.
In conclusion, the mildness and operational simplicity of
this new protocol allowed the preparation of a library of
diaryl selenides. Furthermore, the protocol was applied to
sulfur derivatives with success.
(13) Diaz P. C.I.R.D. GALDERMA, WO 9965872-A1, 1999; Chem.
Abstr. 2000, 132(4), 35910t.
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Org. Lett., Vol. 2, No. 12, 2000