Unexpected C-Se cross-coupling reaction: Copper oxide catalyzed synthesis of symmetrical diaryl selenides via cascade reaction of selenourea with aryl halides/boronic acids

Article abstract of DOI:10.1021/jo102017g

Selenourea is used as an effective selenium surrogate in the C-Se cross-coupling reaction catalyzed by copper oxide nanoparticles under ligand free conditions. This protocol has been utilized for the synthesis of a variety of symmetrical diaryl selenides in good to excellent yields from the readily available aryl halides/boronic acids.

Full text of DOI:10.1021/jo102017g

pubs.acs.org/joc
element in life sciences,5 and hence, their preparation has also
become significant.
Unexpected C-Se Cross-Coupling Reaction: Copper
Oxide Catalyzed Synthesis of Symmetrical Diaryl
Selenides via Cascade Reaction of Selenourea with
Aryl Halides/Boronic Acids
Traditional methods for the formation of a C-Se bond
require photochemical or harsh reaction conditions, such as
the use of polar and toxic solvents like HMPA and high
reaction temperatures.6 To overcome these difficulties,
several metal salts such as palladium-,7 nickel-,8 copper-,9
iron-,10 indium-,11 and lanthanum-based12 catalytic systems
have been studied for the synthesis of diaryl selenides.
In the present paper, we report the failure of our attempts to
transform selenourea (2) into the corresponding N,N0-disubsti-
tuted selenourea (3) by the C-N cross-coupling reaction of aryl
halides (1). However, a very interesting result was obtained from
the 1H NMR spectrum, which showed the formation of a product
which no longer contained the NH protons but only aromatic
hydrogens. Absorption corresponding to the NH was not ob-
served in the infrared spectrum and comparison with the known
compounds. On the basis of these results and the mass spectrum,
we propose that the obtained liquid product has the structure 4.
Recently, heterogeneous catalysts have become attractive
both from economic and industrial points of view as compared
to homogeneous catalysts. The high surface area and reactive
morphologies of nanomaterials allow them to be effective
catalysts for organic synthesis.13 Furthermore, heterogeneous
catalysts have also the advantage of easy product purification
and reusability of the catalyst.
V. Prakash Reddy, A. Vijay Kumar, and K. Rama Rao*
Organic Chemistry Division-I, Indian Institute of Chemical
Technology, Hyderabad-500 007, India
kakulapatirama@gmail.com
Received October 11, 2010
Selenourea is used as an effective selenium surrogate in
the C-Se cross-coupling reaction catalyzed by copper
oxide nanoparticles under ligand free conditions. This
protocol has been utilized for the synthesis of a variety of
symmetrical diaryl selenides in good to excellent yields
from the readily available aryl halides/boronic acids.
In continuation of our interest in the field of cross-
coupling reactions,14 we report herein the CuO nanoparticle-
catalyzed unexpected reaction pattern of selenourea and aryl
(5) (a) Klayman, D. L.; Gunter, H. H. Organoselenium Compounds: Their
Chemistry and Biology; Wiley-Interscience: New York, 1973. (b) Rotruck,
J. T.; Pope, A. L.; Ganther, H. E.; Swanson, A. B.; Hafeman, D. G.;
Hoekstra, W. G. Science 1973, 179, 588. (c) Flohe, L.; Gunzler, E. A.;
Schock, H. H. FEBS Lett. 1973, 32, 132. (d) Shamberger, R. J. Biochemistry
of Selenium; Plenum Press: New York, 1983. (e) Flohe, L.; Andreesen, J. R.;
Brigelius-Flohe, R.; Maiorino, M.; Ursini, F. IUBMB Life 2000, 49, 411.
(6) (a) Suzuki, H.; Abe, H.; Osuka, A. Chem. Lett. 1981, 151. (b) Osuka,
A.; Ohmasa, N.; Suzuki, H. Synth. Commun. 1982, 857. (c) Andersson, C. M.;
Hallberg, A.; Linden, M.; Brattsand, R.; Moldeus, P.; Cotgreave, I. Free
Radic. Biol. Med. 1994, 16, 17. (d) Andersson, C. M.; Hallberg, A.; Hugberg,
T. Adv. Drug Res. 1996, 28, 65.
Organoselenium compounds are not only important re-
agents in organic synthesis1,2 but also serve as potential drug
candidates.3 The biological properties of selenium compounds
have attracted increasing attention due to their antioxidant,
anticancer, antitumor, and antiviral properties.4 In addition,
organoselenium compounds offer chemo-, regio-, and stereo-
selective reactions and selenium is known as a fundamental
(1) (a) Krief, A.; Hevesi, L. Organoselenium Chemistry I; Springer: Berlin,
1988. (b) Comasseto, J. V.; Ling, L. W.; Petragnani, N.; Stefani, H. A.
Synthesis 1997, 373. (c) Organoselenium Chemistry: A Practical Approach;
Back, T. G., Ed.; Oxford University Press: Oxford, UK, 1999. (d) Procter,
D. J. J. Chem. Soc., Perkin Trans. 1 2000, 835.
(7) (a) Nishiyama, Y.; Tokunaga, K.; Sonoda, N. Org. Lett. 1999, 1, 1725.
(b) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V.
J. Organomet. Chem. 2000, 96, 605.
(8) Cristau, H. J.; Chabaud, B.; Labaudiniere, R.; Christol, H. Organo-
metallics 1985, 4, 657.
(2) (a) Braga, A. L.; Ludtke, D. S.; Vargas, F.; Braga, R. C. Synlett 2006,
1453. (b) Braga, A. L.; Vargas, F.; Sehnem, J. A.; Braga, R. C. J. Org. Chem.
2005, 70, 9021. (c) Braga, A. L.; Paixao, M. W.; Ludtke, D. S.; Silveira, C. C.;
Rodrigues, O. E. D. Org. Lett. 2003, 5, 3635. (d) Braga, A. L.; Silva, S. J. N.;
Ludtke, D. S.; Drekener, R. L.; Silveira, C. C.; Rocha, J. B. T.; Wessjohann,
L. A. Tetrahedron Lett. 2002, 43, 7329. (e) Braga, A. L.; Paixao, M. W.;
Marin, G. Synlett 2005, 1975. (f) Braga, A. L.; Ludtke, D. S.; Sehnem, J. A.;
Alberto, E. E. Tetrahedron 2005, 61, 11664.
(3) (a) Sarma, B. K.; Mugesh, G. Org. Biomol. Chem. 2008, 6, 965.
(b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. Chem. Rev. 2004, 104, 6255.
(c) Mugesh, G.; du Mont, W. W.; Sies, H. Chem. Rev. 2001, 101, 2125.
(d) Mugesh, G.; Singh, H. B. Chem. Soc. Rev. 2000, 29, 347.
(4) (a) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2003, 125, 13455.
(b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004, 104, 6255.
(c) Anderson, C.-M.; allberg, A.; Hogberg, T. Adv. Drug Res. 1996, 28, 65.
(d) Clark, L. C.; Combs, G. F.; Turnbull, B. W.; Slate, E. H.; Chalker, D. K.;
Chow, J.; Davis, L. S.; Glover, R. A.; Graham, G. F.; Gross, E. G.;
Krongrad, A.; Lesher, J. L.; Park, K.; Sanders, B. B.; Smith, C. L.; Taylor,
R. J. Am. Med. Assoc. 1996, 276, 1957. (e) Woods, J. A.; Hadfield, J. A.;
McGown, A. T.; Fox, B. W. Org. Biomol. Chem. 1993, 1, 333.
(9) (a) Bhadra, S.; Saha, A.; Ranu, B. C. J. Org. Chem. 2010, 75, 4864. (b)
Singh, D.; Alberto, E. E.; Rodrigues, O. E. D.; Braga, A. L. Green Chem.
2009, 11, 1521. (c) Alves, D.; Santos, C. G.; Paixao, M. W.; Soares, L. C.; de
Souza, D.; Rodrigues, O. E. D.; Braga, A. L. Tetrahedron Lett. 2009, 50,
6635. (d) Saha, A.; Saha, D.; Ranu, B. C. Org. Biomol. Chem. 2009, 7, 1652.
(e) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 915. (f) Kumar, S.;
Engman, L. J. Org. Chem. 2006, 71, 5400. (g) Taniguchi, N. J. Org. Chem.
2007, 72, 1241. (h) Gujadhur, R. K.; Venkataraman, D. Tetrahedron Lett.
2003, 44, 81. (i) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii,
P. V. Tetrahedron Lett. 2003, 44, 7039. (j) Wang, L.; Wang, M.; Huang, F.
Synlett 2005, 2007. (k) Chang, D.; Bao, W. Synlett 2006, 1786. (l) Taniguchi,
N.; Onami, T. Synlett 2003, 829. (m) Taniguchi, N. Synlett 2005, 1687.
(10) Wang, M.; Ren, K.; Wang, L. Adv. Synth. Catal. 2009, 351, 1586.
(11) Ren, K.; Wang, M.; Wang, L. Org. Biomol. Chem. 2009, 7, 4858.
(12) Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Eur.
J. Org. Chem. 2009, 5902.
(13) (a) Pacchioni, G. Surf. Rev. Lett. 2000, 7, 277. (b) Knight, W. D.;
Clemenger, K.; de Heer, W. A.; Saunders, W. A. M.; Chou, Y.; Cohen, M. L.
Phys. Rev. Lett. 1984, 52, 2141. (c) Kaldor, A.; Cox, D.; Zakin, M. R. Adv.
Chem. Phys. 1988, 70, 211.
8720 J. Org. Chem. 2010, 75, 8720–8723
Published on Web 11/23/2010
DOI: 10.1021/jo102017g
r
2010 American Chemical Society

Reddy et al.
JOCNote
SCHEME 1. Synthesis of Symmetrical Diphenyl Selenides
TABLE 2. Diaryl Selenides Synthesis from Various Aryl Halidesa
TABLE 1. Screening of Copper-Catalyzed Synthesis of Symmetrical
Diaryl Selenidesa
copper
source
time temp yieldb
entry
base solvent (h)
Cs2CO3 DMF 24
Cs2CO3 toluene 24
DMSO 24
DMSO 24
Cs2CO3 toluene 24
Cs2CO3 DMSO 24
K3PO4 DMSO 24
(°C)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph-I
Cu2O
120
120
120
120
120
120
120
120
120
120
80
40
rt
80
80
80
80
80
15
0
Cu2O
Cu2O
CuO
CuO
CuO
CuO
CuO
CuO
CuO
KOH
KOH
20
25
trace
18
trace
0
Cs2CO3 THF
KOH DMF
Na2CO3 DMF
24
24
24
10
10
98
68
20
89
21
10
29
41
0c
nano CuO KOH
nano CuO KOH
nano CuO KOH
nano CuO Cs2CO3 DMSO 10
nano CuO Na2CO3 DMSO 10
nano CuO KOH
nano CuO K3PO4 DMSO 10
nano CuO KOH
KOH
nano CuO
DMSO 10
DMSO 10
DMSO 10
toluene 10
DMF
10
DMSO 24
DMSO 24
water 24
DMSO 10
80
80
80
80
25d
0
nano CuO KOH
nano CuO KOH
Ph-B
(OH)2
41
23
24
nano CuO KOH
nano CuO KOH
DMSO 20
DMSO 20
80
100
60
79
aReaction conditions: iodobenzene (2.0 mmol), selenourea (1.0
mmol), catalyst (3.0 mol %), base (2.0 equiv), solvent (2.0 mL). bIsolated
yield. cIn the absence of catalyst. dIn the absence of base.
halides forming symmetrical diphenyl selenides under
ligand-free conditions (Scheme 1). However, to the best of
our knowledge, this is the first report on the synthesis of
symmetrical diphenyl selenides in the absence of any ligand
or cometal catalyst.
Selenourea and iodobenzene were used as model sub-
strates to optimize reaction conditions such as various
copper sources, catalysts, bases, solvents, and temperature
under nitrogen atmosphere (Table 1). First, several copper
oxides were screened (Table 1, entries 1, 4, and 11), and CuO
nanoparticles proved to be preeminent for this tandem
reaction (Table 1, entry 11). Among various bases screened,
KOH and Cs2CO3 were found to be excellent bases (Table 1,
entries 11, 14). Other bases such as Na2CO3 and K3PO4
were tested and led to the formation of lesser amounts
of the desired product. The effect of solvents was also
aReaction conditions: aryl halides (2.0 mmol), selenourea (1.0 mmol),
CuO (3.0 mol %), DMSO (2.0 mL), KOH (2.0 equiv), 80 °C. bIsolated
yield. cAfter 20 h.
investigated, and the highest yield was obtained in DMSO
(Table 1, entry 11), while reaction in solvents such as toluene,
DMF, and water was ineffective (Table 1, entries 16, 18, and
21). The control experiment confirmed that the reaction did
not occur in the absence of the catalyst (Table 1, entry 19) as
well as the base (Table 1, entry 20). When the reaction was
conducted at room temperature and 40 °C, the yields ob-
served were very low (Table1, entries 12 and 13). The ideal
(14) (a) Reddy, V. P.; Swapna, K.; Kumar, A. V.; Rao, K. R. J. Org.
Chem. 2009, 74, 3189. (b) Swapna, K.; Kumar, A. V.; Reddy, V. P.; Rao,
K. R. J. Org. Chem. 2009, 74, 7514. (c) Reddy, V. P.; Kumar, A. V.; Swapna,
K.; Rao, K. R. Org. Lett. 2009, 11, 951. (d) Reddy, V. P.; Kumar, A. V.;
Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697. (e) Reddy, V. P.; Kumar,
A. V.; Swapna, K.; Rao, K. R. Synlett 2009, 2783. (f) Reddy, V. P.; Kumar,
A. V.; Rao, K. R. Chem. Lett. 2010, 39, 212. (g) Reddy, V. P.; Kumar, A. V.;
Rao, K. R. Tetrahedron Lett. 2010, 51, 3181.
J. Org. Chem. Vol. 75, No. 24, 2010 8721

Reddy et al.
JOCNote
TABLE 3. Diaryl Selenide Synthesis from Various Aryl Boronic Acidsa
FIGURE 1. TEM images of (a) fresh nano-CuO particles and (b)
nano-CuO particles after the fourth cycle.
SCHEME 2. Plausible Mechanism for the CuO Nano Particle
Catalyzed C-Se Cross-Coupling of Aryl Halides with Selenourea
(e.g., benzyl bromide) with selenourea, and the corresponding
product was obtained in excellent yields (Table 2, entry 18).
This protocol was also applied for the cross-coupling of
arylboronic acids with selenourea, and the corresponding
diaryl selenides were obtained in high yields with the same
catalyst (Table 3). However, the C-Se cross-coupling of
various substituted aryl boronic acids with selenourea re-
quired longer reaction times and higher temperatures to get
reasonable yields of diaryl selenides, whereas shorter reac-
tion times and lower temperatures led to decreased yields
(Table 1, entries 22-24).
To check the recyclability of the catalyst, after each cycle,
the reaction mixture was allowed to cool and the catalyst was
recovered by ultracentrifugation, washed with ethyl acetate
and acetone, dried under reduced pressure, and reused for
further catalytic reactions. The catalyst maintained its high
level of activity even after the fourth cycle as shown in
Table b (Supporting Information).15
aReaction conditions: aryl boronic acid (2.0 mmol), selenourea (1.0
mmol), CuO (3.0 mol %), DMSO (2.0 mL), KOH (2.0 equiv), 100 °C.
bIsolated yield.
temperature for the reaction was found to be 80 °C. The
influence of the amount of catalyst on the yield of the product
was evaluated. It is observed that 3.0 mol % of copper oxide is
the optimum (Table a, entry 3, Supporting Information).15
The best result was obtained when the reaction was pursued at
80 °C using 3.0 mol % of the CuO nanoparticles in the
presence of KOH (2.0 equiv) and DMSO (2.0 mL).
To explore the scope of copper-catalyzed cascade reaction
of selenourea with various aryl halides was investigated
under the optimized conditions. In general, all the reactions
were very clean, and the diaryl selenides were obtained in
high yields (Table 2). This protocol efficiently coupled
iodobenzenes having electron-donating groups (e.g., Me,
Et, and OMe) with selenourea to produce the corresponding
products in excellent yields (Table 2, entries 4, 6, and 7),
whereas in the presence of an electron-withdrawing group
(NO2) a slight decrease in the yield of the diaryl selenide
(Table 2, entry 9) was observed.
Utilizing these conditions, various heteroaromatic iodides
allowed reaction with selenourea to give the corresponding
diaryl selenides in excellent yields (Table 2, entries 11, 12, 14, 15,
and 17). The reaction of heteroaromatic bromides with sele-
nourea required a longer reaction time to achieve reasonable
yields of diaryl selenides (Table 2, entries 13 and 16). Among
the 2-iodo/3-iodothiopene and 5-methyl-2-iodothiopenes, the
activated ones give a higher yield (Table 2, entries 12, 14,
and 15). Iodobenzene was found to be a more reactive substrate
than bromo- and chlorobenzenes (Table 2, entries 1-3).
Moreover, the formation of bis(3-bromophenyl)selane as
the major product in the reaction of m-bromoiodobenzene
implied that there was good chemoselectivity between iodo
and bromo substituents (Table 2, entry 10). This protocol
was also applied for the cross-coupling of alkyl bromide
These reactions involve a heterogeneous process. TEM
images of the catalyst indicated no change before and after
the reaction, which further confirmed the heterogeneous
nature of the catalyst (Figure 1).
A plausible mechanism for the CuO nanoparticle cata-
lyzed C-Se cross-coupling of aryl halides and selenourea is
shown in Scheme 2.16 Oxidative addition of aryl halide
to copper oxide nanoparticles leads to the formation of a,
which undergoes reaction with selenourea to give the inter-
mediate b, which gets transformed to the intermediate Se-
arylisoselenouronium salt c by reductive elimination, and
this upon hydrolysis in the reaction mixture produces a
benzeneselenate moiety and urea. In this step, urea is hydro-
lyzed in situ to produce carbon dioxide and ammonia as the
final products.17 Oxidative addition of aryl iodide to copper
oxide nanoparticles leads to the formation of a, which
undergoes reaction with benzeneselenate anion to give the
intermediate d and that completes the catalytic cycle to
produce diaryl selenide by reductive eliminaton.
(16) Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra,
R.; Saha, P.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 1971.
(17) Fischer, R. B.; Peters, D. G. Quantitative Chemical Analysis, 3rd ed.;
W. B. Saunders Co.: Philadelphia, 1968.
(15) See the Supporting Information.
8722 J. Org. Chem. Vol. 75, No. 24, 2010

Reddy et al.
JOCNote
In summary, this is the first reported reaction of aryl
halides/boronic acids with selenourea for the synthesis of
symmetrical diaryl selenides catalyzed by CuO nanoparticles
under ligand-free conditions in the absence of any additive.
Various aryl halides/boronic acids underwent cross-coupling
with selenourea to give the corresponding products in ex-
cellent yields. The catalyst is cheap, air stable, and recyclable
and functions under ligand-free conditions.
mixture of ethyl acetate/water (20 mL) was added. The com-
bined organic extracts were dried with anhydrous Na2SO4. The
solvent and volatiles were completely removed under reduced
pressure to give the crude product, which was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate) to afford the corresponding coupling product in 98%
1
yield: colorless oil; H NMR (CDCl3, 200 MHz) δ 7.43-7.41
(m, 4H), 7.24-7.22 (m, 6H); 13C NMR (CDCl3, 50 MHz) δ
132.9, 131.3, 129.2, 127.2.
Experimental Section
Acknowledgment. V.P.R. thanks CSIR and A.V.K.
thanks UGC, New Delhi, for the award of fellowships.
General Procedure. To a stirred solution of iodobenzene (2.0
mmol) and selenourea (1.0 equiv) in dry DMSO (2.0 mL) at rt
was added nano CuO (3.0 mol %) followed by KOH (2.0 equiv)
and the mixture heated at 80 °C for 10 h. The progress of the
reaction was monitored by TLC. After the reaction was com-
plete, the reaction mixture was allowed to cool, and a 1:1
Supporting Information Available: Detailed experimental
procedures and compound characterization data for all pro-
ducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8723