Al2O3-Supported Cu-catalyzed electrophilic substitution by PhSeBr in organoboranes, organosilanes, and organostannanes. A protocol for the synthesis of unsymmetrical diaryl and alkyl aryl selenides

Article abstract of DOI:10.1021/jo100755g

(Figure Presented) Alumina-supported copper sulfate efficiently catalyzes electrophilic substitution in organoborane, organosilanes, and organostannanes by phenylselenium bromide providing a novel and efficient route to the synthesis of unsymmetrical diaryl and alkyl aryl selenides. A series of aryl, alkyl, and heteroaryl phenyl selenides were obtained in high yields. The catalyst is inexpensive, eco- and user-friendly, and recyclable. The mechanism involving Cu-assisted nucleophilic displacement of Br in PhSeBr by mild nucleophiles is described.

Full text of DOI:10.1021/jo100755g

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SCHEME 1. Cu-Catalyzed Carbon-Selenium Bond Formation
Al2O3-Supported Cu-Catalyzed Electrophilic
Substitution by PhSeBr in Organoboranes,
Organosilanes, and Organostannanes. A Protocol for
the Synthesis of Unsymmetrical Diaryl and Alkyl
Aryl Selenides
Sukalyan Bhadra, Amit Saha, and Brindaban C. Ranu*
Department of Organic Chemistry, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata-700032, India
ocbcr@iacs.res.in
Received April 19, 2010
or aryl boronic acids under oxygen atmosphere (oxidative
coupling)4 in the presence of a transition metal catalyst.
Another is the electrophilic substitution by ArSeþ (ArSeX,
ArSeCN) in stronger nucleophiles such as aryl lithium, aryl
Grignard reagent, or aryl mercurals.5 However electrophilic
substitution by ArSeþ in milder nucleophiles like aryl boro-
nic acids, aryl siloxanes, and aryl stannanes is rare. Only one
such reaction of phenylselenyl chloride and vinyl boronic
acid/ester in the presence of ionic liquid has been reported by
Kabalka et al.6 Thus, we considered it interesting to investi-
gate electrophilic substitution by PhSeþ in readily available
milder nucleophilic reagents using a simple catalyst. This led
us to report here a general reaction of phenylselenium bro-
mide with aryl, alkyl, or heteroaryl boronic acids/siloxanes/
stannanes using our recently developed heterogeneous
alumina-supported copper(II) catalyst7 (Scheme 1). This
catalyst is very easy to prepare, inexpensive, and environ-
mentally friendly.
To optimize the reaction conditions the coupling of phe-
nylselenyl bromide with phenyl boronic acid/phenyl trimeth-
oxysilane/phenyl tributylstannane using different solvents
and base at varied temperatures in the presence of Cu/Al2O3
was studied. The best result was obtained by using 4 mol %
of Cu/Al2O3 catalyst and K2CO3 in THF (Table 1, entries 5,
10, and 13). In the absence of catalyst (Table 1, entries 6, 11,
and 14) the reaction did not proceed at all in the case of
siloxane and stannane and occurred marginally (15%) with
phenyl boronic acid. The reactions with either Al2O3 or
Alumina-supported copper sulfate efficiently catalyzes
electrophilic substitution in organoborane, organosi-
lanes, and organostannanes by phenylselenium bromide
providing a novel and efficient route to the synthesis of
unsymmetrical diaryl and alkyl aryl selenides. A series of
aryl, alkyl, and heteroaryl phenyl selenides were obtained
in high yields. The catalyst is inexpensive, eco- and user-
friendly, and recyclable. The mechanism involving Cu-
assisted nucleophilic displacement of Br in PhSeBr by
mild nucleophiles is described.
The phenylselenylation is a useful process in organic syn-
thesis as selenium compounds are of much potential as
anticancer and antioxidant agents.1 The existing methods
for the synthesis of aryl selenides are based on primarily two
types of reactions. The most common one is the nucleophilic
addition of ArSe- to aryl halides2 or aryl diazonium salts3
(1) (a) Shine, H. In Organic Selenium Compounds: Their Chemistry and
Biology; Klayman, D. L. J., Gunther, W. H. H., Eds.; Wiley-Interscience:
New York, 1973; pp 941-962. (b) Castla, L.; Perkins, M. J. In The Chemistry
of Organic Selenium and Tellurium Compounds; Patai, S., Ed.; John Wiley and
Sons: New York, 1987; Vol. 2, pp 657-673. (c) Weng, X.; Ren, L.; Weng, L.;
Huang, J.; Zhu, S.; Zhou, X.; Weng, L. Angew. Chem., Int. Ed. 2007, 46, 8020–
8023.
(2) (a) Cristan, H. J.; Chabaud, B.; Labaudiniere, R.; Christol, H.
Organometallics 1985, 4, 657–661. (b) Millois, C.; Diaz, P. Org. Lett. 2000,
2, 1705–1708. (c) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 915–920.
(d) Kumar, S.; Engman, L. J. Org. Chem. 2006, 71, 5400–5403. (e) Fukuzawa,
S.-i.; Tanihara, D.; Kikuchi, S. Synlett 2006, 2145–2147. (f) Bonaterra, M.;
Martin, S. E.; Rossi, R. A. Tetrahedron Lett. 2006, 47, 3511–3515. (g) Ajiki,
K.; Hirano, M.; Tanaka, K. Org. Lett. 2005, 7, 4193–4195. (h) Beletskaya,
I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V. J. Organomet. Chem.
2000, 605, 96–101. (i) Saha, A.; Saha, D.; Ranu, B. C. Org. Biomol. Chem.
2009, 7, 1652–1657.
(4) (a) Taniguchi, N. J. Org. Chem. 2007, 72, 1241–1245. (b) Wang, L.;
Wang, M.; Huang, F. Synlett 2005, 2007–2010.
(5) (a) Campbell, T. W.; Mccullough, J. D. J. Am. Chem. Soc. 1945, 67,
1965–1966. (b) Greenburg, B.; Gould, E. S.; Burlant, Wm. J. Am. Chem. Soc.
1956, 78, 4028–4029. (c) Godoi, B.; Speranca, A.; Back, D. F.; Brandao, R.;
Nogueira, C. W.; Zeni, G. J. Org. Chem. 2009, 74, 3469–3477. (d) Tomoda,
S.; Takeuchi, Y.; Nomura, Y. Chem. Lett. 1982, 253–256. (e) Cohen, R. J.;
Fox, D. L.; Salvatore, R. N. J. Org. Chem. 2004, 69, 4265–4268.
(6) Kabalka, G. W.; Venkataiah, B. Tetrahedron Lett. 2002, 43, 3703–
3705.
(7) Bhadra, S.; Sreedhar, B.; Ranu, B. C. Adv. Synth. Catal. 2009, 351,
2369–2378.
(8) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009,
11, 951–953.
(9) Singh, D.; Alberto, E. E.; Rodrigues, O. E. D.; Braga, A. L. Green
Chem. 2009, 11, 1521–1524.
(10) Gao, S.-Y.; Chittimalla, S. K.; Chuang, G. J.; Liao, C.-C. J. Org.
Chem. 2009, 74, 1632–1639.
(11) Ranu, B. C.; Mandal, T. J. Org. Chem. 2004, 69, 5793–5795.
(3) Evers, M. J.; Christiaens, L. E.; Renson, M. J. J. Org. Chem. 1986, 51,
5196–5198.
4864 J. Org. Chem. 2010, 75, 4864–4867
Published on Web 06/18/2010
DOI: 10.1021/jo100755g
r
2010 American Chemical Society

Bhadra et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
TABLE 2. Copper Catalyzed Phenylselenylation of Organyl Boronic
Acids
entry
RZ
solvent
base
temp (ꢀC) time (h) yield (%)
1
2
3
4
5
6
7
8
9
PhB(OH)2
DMF K2CO3
DMSO K2CO3
H2O K2CO3
toluene K2CO3
120
130
100
110
70
70
70
70
70
70
70
120
70
70
120
16
16
16
16
8
18
16
16
16
9
18
16
8
18
16
70
50
0
20
92
15b
84
42
30
88
0b
THF
THF
THF
THF
THF
K2CO3
K2CO3
Cs2CO3
K3PO4
NaOH
K2CO3
K2CO3
10 PhSi(OMe)3 THF
11
12
13 PhSnBu3
14
15
THF
DMF K2CO3
55
86
0b
THF K2CO3
THF K2CO3
DMF K2CO3
48
aReactions were carried out in the presence of 4 mol % of Cu/Al2O3
catalyst unless otherwise stated. bReactions were carried out in the
abesence of Cu/Al2O3 catalyst.
CuSO4 alone or a mixture of Al2O3 and CuSO4 also provided
the same results as observed in the absence of catalyst.
Thus in a typical experimental procedure, a mixture of
phenylselenyl bromide and organo-boronic acid/siloxane/
stannane was heated in THF at 70 ꢀC in the presence of Cu/
Al2O3 and K2CO3 for a period of time as required to com-
plete the reaction (TLC) to provide the corresponding
selenide. Standard workup followed by purification provided
the product. The results were summarized in Tables 2-4.
The phenylselenylation of organo-boronic acids was demon-
strated in Table 2. A variety of substituted phenyl boronic
acids participated in this reaction. Both electron-donating
and electron-withdrawing groups in the phenyl ring of
boronic acids are equally effective. The difluorophenyl
boronic acid also provided the corresponding product with-
out any difficulty. The naphthyl and heteroaryl such as
furanyl, thiophenyl, and pyridinyl boronic acids are compa-
tible with this reaction. These fluorophenyl and heteroaryl
selenides may be of potential for biological activity.1
The alkyl boronic acid also underwent reaction by this
procedure. The phenylselenylation of aryl, vinyl, and allyl
siloxanes and stannanes was achieved in high yields with the
same catalyst (Tables 3 and 4).
In general the reactions are very clean and high yielding. A
wide range of functionalized unsymmetrical diaryl, hetero-
aryl-aryl, and alkyl-aryl selenides were obtained by this
procedure. This procedure is compatible with a variety of
functionalities such as OMe, Cl, F, COMe, CN, etc. This
protocol has enormous scope for an easy access to a library
of organoselenides starting from any of the organo-boranes,
silanes, and stannanes. The Cu/Al2O3 catalyst is very robust,
nonair-sensitive, and user-friendly. No appreciable leaching
of catalyst was detected as measured by ICP-MS (inductively
coupled plasma mass spectrometry) (Cu content of the fresh
catalyst: 0.517 mmol g-1; and that after 7th cycle: 0.503
mmol g-1) and the catalyst is recycled seven times without
any appreciable loss of efficiency.
aIsolated yield of pure product.
at 77 K resulting from the coupling of the unpaired electron
with the nuclear spin of copper(II) (Figure 1). The g values
of the fresh and used catalyst are g = 2.41367, 2.5408 and
g^ = 2.1406, indicating a tetragonally distorted octahedral
To investigate the mechanism of the reaction a series of
experiments were conducted. The X-band EPR (electron
paramagnetic resonance) spectrum of the fresh copper cata-
lyst shows four well-defined hyperfine lines for solid sample
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Bhadra et al.
JOCNote
TABLE 3. Copper Catalyzed Phenylselenylation of Organo Silanes
FIGURE 1. The X-band EPR spectral pattern of Cu2þ in (a) fresh
catalyst, (b) used catalyst, and (c) intermediate complex 2.
SCHEME 2. Mechanistic Proposal
aIsolated yield of pure product.
TABLE 4. Copper Catalyzed Phenylselenylation of Organo Stannanes
complex is also not unprecedented.13 The EPR spectral
pattern of this intermediate complex exhibited the g values
as g3 = 2.055, g2 = 2.124, and g1 = 2.212 which are indica-
tive of an octahedral environment with a rhombic distortion
at the metal center.
To check an alternative possibility of the reaction pathway
we also treated the Cu catalyst with phenylboronic acid. The
reaction residue did not show any change in FTIR and EPR
spectra from those of fresh catalyst indicating no reaction.
This clearly suggests that an interaction of substrate PhSeBr
with the copper catalyst is the first step of the reaction to give
an intermediate complex 2 giving rise to a rhombic distor-
tion of the copper(II) coordination geometry. The UV-DRS
(ultra violet diffuse electron spectrometry) experiments of
the fresh and used catalyst show the band at >750 nm while a
aIsolated yield of pure product.
geometry for Cu(II).12 The regenerated catalyst also shows a
very similar axial EPR spectrum as observed in the freshly
prepared catalyst. When the fresh catalyst was treated with
phenylselenyl bromide in THF a dirty white complex 2
(Scheme 2) was obtained. The FTIR of this complex shows
an additional band at 2800-3000 cm-1 corresponding to
the aromatic C-H stretching frequencies indicating the
addition of PhSeBr with Cu(II) center (see the Supporting
Information). These peaks disappeared in the FTIR spec-
trum of the used catalyst. The formation of this type of
(12) (a) Matsuoka, M.; Ju, W.-S.; Takahashi, K.; Yamashita, H.; Anpo,
M. J. Phys. Chem. B 2000, 104, 4911–4915. (b) Kantam, M. L.; Chakravarti,
R.; Neelima, B.; Arundhati, R.; Sreedhar, B. Appl. Catal., A 2007, 333,
136–142.
(13) (a) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G. T.;
Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948–9949. (b) Choudary, B. M.;
Madhi, S.; Kantam, M. L.; Sreedhar, B.; Iwasawa, Y. J. Am. Chem. Soc.
2004, 126, 2292–2293.
4866 J. Org. Chem. Vol. 75, No. 14, 2010

Bhadra et al.
JOCNote
appreciable leaching of catalyst make this procedure more
attractive for the synthesis of organoselenides.
Experimental Section
General Experimental Procedure for the Synthesis of Organo-
selenides: Representative Procedure for Diphenyl Selenide by
Phenylselenylation of Phenyl Boronic Acids (Table 2, Entry 1).
To a solution of phenylselenyl bromide (236 mg, 1 mmol) and
phenyl boronic acids (147 mg, 1.2 mmol) in THF (4 mL) was
added K2CO3 (276 mg, 2 mmol) and Cu/Al2O3 catalyst (80 mg,
4 mol %) and the mixture was heated at 70 ꢀC (oil bath) for 8 h.
The reaction mixture was allowed to cool, extracted with Et2O
(3 ꢀ 20 mL), and washed with brine. The organic phase was
dried (Na2SO4) and evaporated to leave the crude product,
which was purified by column chromatography over silica gel
(hexane) to provide pure diphenyl selenide as a colorless oil
(215 mg, 92%). The spectroscopic data (1H NMR and 13C NMR)
of this product are in good agreement with those of an authentic
sample.2i After workup the residual catalyst was washed with
water (5 ꢀ 3 mL) followed by acetone (3 ꢀ 4 mL). The solid was
then dried at 100 ꢀC for 8 h for further use. The catalyst was
recycled 7 times without any appreciable loss of activity (see the
recyclability chart in the Supporting Information).
This procedure was followed for all the reactions listed in
Table 2 and for phenylselenylation of organo-siloxanes (in the
presence of 1 M THF solution of TBAF, 1.2 mL) and stannanes
listed in Tables 3 and 4, respectively. Although the representa-
tive procedure is based on a 1 mmol scale reaction, it has been
scaled up to 10 mmol with reproducible results. The compounds
are of high purity as checked by 13C NMR.
The known compounds were identified by comparison of
their spectra with those of authentic samples (see references in
Tables 2-4). The unknown compounds were properly charac-
terized by their spectroscopic data (IR, 1H NMR, and 13C
NMR) provided in the Supporting Information.
FIGURE 2. UV-vis-DR spectrum of (a) fresh catalyst, (b) inter-
mediate complex 2, and (c) used catalyst.
blue shift (680-700 nm) was observed for the intermediate
complex (Figure 2).
This further supports the presence of octahedral geometry
around Cu(II).12b,14 Thus the formation of copper(II) sele-
nide complex 2 as intermediate is proposed. Subsequent
addition of RZ [Z = B(OH)2, Si(OR1)3, SnBu3] at 2 followed
by aryl-selenium bond formation furnishes the intermediate
4 via a transient 3 where R interacts with the Se center being
assisted by Cu(II) catalyst (Scheme 2). We speculate that a
copper-assisted nucleophilic displacement13,15 occurs at the
selenium center of PhSeBr by the mild carbon nucleophiles
(boronic acids, silanes, stannanes, etc.). The elimination of
PhSeR from the coordination sphere of Cu(II) regenerates
the catalyst, which initiates the next cycle.
In conclusion, we have developed a very efficient and
general protocol for the synthesis of unsymmetrical aryl-
aryl, alkyl-aryl, and heteroaryl-aryl selenides by the reac-
tion of phenylselenyl bromide and any of the organo-boronic
acids, siloxanes, and stannanes catalyzed by heterogeneous
Cu(II)/Al2O3 catalyst. Such a wide scope demonstrated by a
single strategy is noteworthy. The most significant feature of
this protocol is the involvement of hitherto unexplored
electrophilic substitution by PhSeþ in milder carbon nucleo-
philes such as aryl boranes, silanes, and stannanes. The
advantages of high yields, simplicity of operation, scaling
up to multigram quantities, easy availability and recyclabil-
ity of catalyst, and environmental acceptability with no
Acknowledgment. This investigation has enjoyed finan-
cial support from CSIR, Government of India, New Delhi.
We also acknowledge the help of Dr. T. K. Paine and
Mr. S. Paria of this Institute for recording EPR spectrum for us.
Supporting Information Available: Procedure for the pre-
paration of intermediate complex 2 (Scheme 2), FTIR spectra of
fresh catalyst, used catalyst, and intermediate complex 2 and
catalyst recyclability chart, characterization data (IR, 1H, and 13
C
NMR spectroscopic data, elemental analysis report) of the pro-
ducts in entries 9, 11, and 13 in Table 2, and copies of 1H and 13
C
NMR spectra of all products listed in Tables 2-4. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Marion, M. C.; Garbowski, E.; Primet, M. J. Chem. Soc., Faraday
Trans. 1990, 86, 3027–3032.
(15) Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239–6242.
(16) Zheng, Y.; Bao, W.; Weiliang, Z. Y. Synth. Commun. 2000, 30, 1731–
1736.
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