A general method for the formation of diaryl selenides using copper(I) catalysts

Article abstract of DOI:10.1016/S0040-4039(02)02480-2

We report a mild, palladium-free synthetic protocol for the cross coupling reaction of aryl iodides and phenyl selenol using 10 mol% CuI/neocuproine, NaOt-Bu or K₂CO₃ as base, in toluene, at 110°C. Using this protocol, we show that a variety of diaryl selenides can be synthesized in good yields from commercially available aryl iodides.

Full text of DOI:10.1016/S0040-4039(02)02480-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 81–84
A general method for the formation of diaryl selenides using
copper(I) catalysts
Rattan K. Gujadhur and D. Venkataraman*
Department of Chemistry, University of Massachusetts, Amherst, 710 North Pleasant Street, Amherst, MA 01003, USA
Received 3 October 2002; revised 30 October 2002; accepted 5 November 2002
Abstract—We report a mild, palladium-free synthetic protocol for the cross coupling reaction of aryl iodides and phenyl selenol
using 10 mol% CuI/neocuproine, NaOt-Bu or K2CO3 as base, in toluene, at 110°C. Using this protocol, we show that a variety
of diaryl selenides can be synthesized in good yields from commercially available aryl iodides. © 2002 Elsevier Science Ltd. All
rights reserved.
Diaryl selenides have attracted considerable interest
because of their potential as anticancer and antioxidant
agents.1 They are also key intermediates in the synthesis
of a plethora of biologically and pharmaceutically
important selenium compounds such as selenonium
salts, selenoxides, selenimines, and selenide dihalides.2
In recognition of their importance, various synthetic
methods for the formation of diaryl selenides have been
reported in the literature.3 Earlier methods often
require photochemical or harsh reaction conditions
such as the use of polar, toxic solvents such as HMPA
and high reaction temperatures.4 Other reported proto-
cols include the reaction of aryl halide and benzenesele-
nate anion in liquid ammonia under UV light and the
reaction of sodium selenide with arenediazonium salts.5
In recent years, only a handful of reports have
appeared in the literature with synthetic protocols for
the formation of arylꢀselenium bonds that are general,
mild and tolerant. In 1985, Cristau and co-workers first
showed that aryl selenides can be obtained by a cross-
coupling reaction of aryl halides and sodium benzenese-
lenolate using Ni(II)-based catalysts.6 In 2000, Millois
and Diaz modified and extended Cristau’s method to
accommodate diaryl diselenide as a starting material
instead of sodium benzeneselenolate.7 Very recently, the
groups of Nishiyama and Beletskaya have indepen-
dently reported protocols for the cross coupling reac-
tion of aryl iodides and PhSeSnBu3 using
palladium-based catalysts.8
In the past 5 years, there has been a resurgence in
interest in developing mild synthetic methods based on
copper-based catalysts as an alternative to palladium(0)
catalysts for the formation of arylꢀcarbon and
arylꢀheteroatom bonds. In this regard, the D.V. group9
and others10,11 have reported copper-based methods for
Table 1. Optimization of the reaction between aryl iodide
and phenyl selenol
Entry
Base
GC yield (%)
1
2
3
4
5
6
7
CsF
B5
B5
B10
70
70
82
Cs2CO3
KOt-Bu
K2CO3
Na2CO3
K3PO4
NaOt-Bu
the
formation
of
arylꢀcarbon,
arylꢀnitrogen,
arylꢀoxygen and arylꢀsulfur bonds. In addition to being
simple and mild, these protocols also accommodate
substrates that do not undergo coupling by palladium
catalysis.12 Moreover, in comparison to palladium, cop-
per-based catalysts are quite attractive from an eco-
nomic standpoint, especially in large and industrial
scale syntheses.13 We now extend the utility of copper-
based catalysts for the formation of aryl-selenium
bonds.
92
* Corresponding author. Tel.: 413-545-2028; fax: 413-545-4490;
e-mail: dv@chem.umass.edu
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02480-2

82
R. K. Gujadhur, D. Venkataraman / Tetrahedron Letters 44 (2003) 81–84
well-defined Cu(neocuproine)(PPh3)Br, since it gave
identical results and dispenses with the need to synthe-
size the complex. After having established the efficacy
of the CuI/neocuproine catalytic system for the forma-
tion of arylꢀselenium bonds, we then studied the effect
of the base on these reactions (see Table 1).
We found that NaOt-Bu was the most effective base for
this reaction. In contrast, KOt-Bu was not an effective
base in our protocol, similar to what we had observed
for the formation of arylꢀsulfur bonds. Milder bases
such as K3PO4, K2CO3 and Na2CO3 provided diphenyl
selenide in moderate yields. Other mild bases such as
CsF and Cs2CO3 were ineffective. In our protocol, we
then replaced iodobenzene with bromobenzene. By GC,
in addition to both the starting materials, significant
amount of diphenyl diselenide was observed, pre-
sumably from the oxidation of phenyl selenol. This
indicated that the reaction was selective to iodides.
We began the investigation of the cross-coupling reac-
tion between aryl iodides and phenyl selenol using 10
mol% CuI/neocuproine14 with NaOt-Bu as the base
and toluene as the solvent. We were pleased to find that
using this protocol, in 24 h, the reaction between
iodobenzene and phenyl selenol was complete. The
ligand, neocuproine, was found to be essential for the
reaction, since its absence gave no conversion to the
desired product. If in the reaction protocol neocuproine
was replaced by phenanthroline, diphenyl selenide was
obtained in a lower yield (70% by GC). Moreover, the
reaction with the well-defined complex Cu-
(neocuproine)(PPh3)Br showed complete conversion to
the product after the same period of time. We chose to
use CuI/neocuproine as our catalyst instead of the
Table 2. Reaction of electron-rich aryl iodides and phenyl
selenol
Using our protocol,† we were able to couple phenyl
selenol with electron-rich aryl iodides in very good
yields (Table 2). We were able to couple sterically
hindered iodides such as those with ortho-functionali-
ties (entries 3, 5, 7 and 11), as well as aryl iodides
containing heteroatoms (entry 8 and 10). When o-
iodoaniline was used as the aryl halide, in addition to
the desired selenide, we observed products arising from
the self-coupling of o-iodoaniline. This problem also
persisted with K3PO4. However, when K2CO3 was used
† General procedure: In an argon-filled glove box, a Pyrex glass tube
(2.5 cm in diameter) equipped with a Teflon stir bar, was charged
with sodium tert-butoxide (Acros, 3.0 mmol), CuI (10 mol% with
respect to the aryl iodide), and neocuproine (10 mol% with respect
to the aryl iodide). The tube was then sealed with a rubber septum,
taken out of the glove box and phenol selenol (2.2 mmol), the aryl
iodide (2.00 mmol) and toluene (4.0 mL) were injected into the tube
through the septum. The contents were then stirred at 110°C for 24
h. The reaction mixture was then cooled to room temperature and
filtered to remove any insoluble residues. The filtrate was concen-
trated in vacuo; the residue was purified by flash column chro-
matography on silica gel to obtain the analytically pure product.
Spectroscopic data for selected products from Table 2.
Entry 6: The general procedure was used to convert 4-n-butyl-
iodobenzene and phenyl selenol to the title product. Purification by
flash chromatography (hexane as the eluent) gave the analytically
pure product as a transparent oil (464 mg, 80% yield). 1H NMR
(300 MHz, CDCl3) l 7.35–7.31 (m, 4H), 7.18–7.13 (m, 3H), 7.03–
6.99 (m, 2H), 2.53 (t, 2H), 1.53–1.18 (m, 4H), 0.87 (t, 3H). 13C
NMR (75 MHz, CDCl3) l 142.56, 133.65, 132.14, 131.93, 129.49,
129.17, 127.0, 126.86, 32.25, 33.46, 22.31, 13.92 (C8). Anal. calcd for
C16H18Se: C, 66.43; H, 6.27; Found C, 66.68; H, 6.54%.
Entry 10: The general procedure was used to convert 1-(4-
iodophenyl)pyrrole and phenyl selenol to the title product. Purifica-
tion by flash chromatography (hexane as the eluent) gave the
analytically pure product as a white solid (450 mg, 76% yield). 1H
NMR (300 MHz, CDCl3) l 7.48–7.38 (m, 3H), 7.26–7.19 (m, 6H),
7.07 (t, J=4.3, 2H), 6.28 (t, J=4.3, 2H). 13C NMR (75 MHz,
CDCl3) l 134.54 (C3), 133.35, 132.68, 131.85, 129.40, 127.38, 125.0,
121.16, 119.13, 110.70. Anal. calcd for C16H13NSe: C, 64.43; H,
4.39. Found C, 64.35; H, 4.56. Melting point: 86–88°C. All other
compounds reported in Tables 2 and 3 are known.

R. K. Gujadhur, D. Venkataraman / Tetrahedron Letters 44 (2003) 81–84
83
as the base, we were able to isolate 1-amino-2-phenylse-
lanyl-benzene in 60% yield (entry 12). With electron-
poor aryl iodides, in addition to the desired diaryl
selenides, we observed diaryl diselenides if NaOt-Bu or
K3PO4 was used. In addition, with NaOt-Bu, transes-
terifcation products were observed when aryl halides
with ester groups were used. We found that these
problems can be avoided if K2CO3 was used instead of
NaOt-Bu or K3PO4. Using this modified protocol we
were able to obtain a variety of diaryl selenides from
electron-poor aryl halides (Table 3). The protocol toler-
ates even base sensitive groups such as esters and
ketones (entries 3, 4, and 6).
Dreyfus New Faculty Award and an NSF CAREER
Award (CHE-0134287).
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as the base, and toluene as the solvent for electron-rich
aryl iodides. For electron-poor aryl iodides, we recom-
mend the use of K2CO3 in the place of NaOt-Bu. Our
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readily available phenyl selenols. We are in the process
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reporting on them shortly.15
Acknowledgements
The University of Massachusetts, Amherst start-up
funds provided the financial support for this research.
D.V. gratefully acknowledges a Camille and Henry
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diphenyl selenide, using the methodology developed by
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in stoichiometric amounts, with triethylamine as the base
and dichloromethane as the solvent.