Imidazolium-containing diselenides for catalytic oxidations with hydrogen peroxide and sodium bromide in aqueous solutions

Article abstract of DOI:10.1016/j.tet.2012.08.004

The design and synthesis of imidazolium-containing diselenides 4a-c is described. The introduction of the N-methylimidazolium group gives freely soluble compounds in water, unlike the majority of common organic diselenides. Catalytic amounts of 4a-c effectively promote bromination of organic substrates using a safe and inexpensive NaBr/H₂O₂ system in water. Kinetics experiments revealed that the bromination of 4-pentenoic acid has a first-order dependence with respect to both NaBr and H₂O₂ concentrations The rate of reaction was also sensitive to the pH of the solution. Preparative reactions showed that, compared to 4a, diphenyl diselenide 5 was a poor catalyst and the ionic liquid 1-benzyl-3-methylimidazolium bromide 6 showed no catalytic activity with H₂O₂ indicating synergy from the combined functionality.

Full text of DOI:10.1016/j.tet.2012.08.004

Tetrahedron 68 (2012) 10476e10481
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Imidazolium-containing diselenides for catalytic oxidations with hydrogen
peroxide and sodium bromide in aqueous solutions
,
,
b,
Eduardo E. Alberto a b, Antonio L. Braga c , Michael R. Detty
*
*
a Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
b Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
c
ꢀ
Departamento de Química, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2012
Received in revised form 30 July 2012
Accepted 1 August 2012
Available online 7 August 2012
The design and synthesis of imidazolium-containing diselenides 4aec is described. The introduction of
the N-methylimidazolium group gives freely soluble compounds in water, unlike the majority of common
organic diselenides. Catalytic amounts of 4aec effectively promote bromination of organic substrates
using a safe and inexpensive NaBr/H2O2 system in water. Kinetics experiments revealed that the bro-
mination of 4-pentenoic acid has a first-order dependence with respect to both NaBr and H2O2 con-
centrations The rate of reaction was also sensitive to the pH of the solution. Preparative reactions showed
that, compared to 4a, diphenyl diselenide 5 was a poor catalyst and the ionic liquid 1-benzyl-3-
methylimidazolium bromide 6 showed no catalytic activity with H2O2 indicating synergy from the
combined functionality.
Keywords:
Sodium bromide
Hydrogen peroxide
Water-soluble diselenide
Catalyst
Ó 2012 Elsevier Ltd. All rights reserved.
Bromination
1. Introduction
diorganylselenides with Br2,7 halogenation via the combination of
a halosuccinimide with PhSeSePh or PhSeCl,8 and bromination via
Halogenated compounds are key synthons in organic trans-
formations and frequently exhibit biological activity.1 However, in
most protocols their synthesis involves the use of molecular halo-
gen or other sources of positive halogen, both of which can have
adverse impact on health and the environment. Currently there is
increased interest in developing new halogenation methods that
are efficient, environmentally benign, and non-toxic.2
Reactions using H2O2/bromide salts to replace bulk Br2 as a re-
agent are attractive for organic bromination reaction: (1) H2O2 is an
inexpensive oxidizing agent, (2) it decomposes to oxygen and wa-
ter, and (3) bromide is a safe and inexpensive halogen precursor
relative to toxic and corrosive Br2.2c However, even though H2O2 is
a potent oxidizing agent thermodynamically, reactions with H2O2
can be sluggish kinetically limiting its application. Organo-
chalcogen compounds have been extensively employed as cata-
lysts/activators of H2O2 in many diverse transformations, including
epoxidation reactions,3 BaeyereVilliger oxidations,4 and oxidations
of thiols and sulfides5 among others.6 Organoselenium catalysts
have also found synthetic utility for the halogenation of organic
compounds in several different ways: bromination via reaction of
the activation of H2O2 for the oxidation of sodium bromide to ‘Brþ’
species using selenoxides or aryl seleninic acids as catalysts.9,10
As a continuation of our interest in the use of organochalcogen
11
compounds as catalysts for the activation of H2O2 we describe
herein the preparation of new water-soluble diselenides 4aec
(Chart 1). These compounds were evaluated as catalysts to pro-
mote bromination reactions with H2O2/NaBr in aqueous solutions.
The incorporation of the N-methylimidazolium group as in 4aec
greatly enhances water solubility. This feature in synergism with
the diselenide functionality improves the catalytic activity of 4aec
when compared to diphenyl diselenide 5 or to the ionic liquid 1-
benzyl-3-methylimidazolium bromide 6.
* Corresponding authors. Tel.: þ1 716 645 4228; fax: þ1 716 645 6963 (M.R.D.);
tel.: þ55 48 3721 6844 (A.L.B.); e-mail addresses: albraga@qmc.ufsc.br (A.L. Braga),
mdetty@buffalo.edu, mdetty@acsu.buffalo.edu (M.R. Detty).
Chart 1. Structures of catalysts used in this study.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.004

E.E. Alberto et al. / Tetrahedron 68 (2012) 10476e10481
10477
2. Results and discussion
include in this kinetic study in D2O. The relative catalytic activity of
5 is described in later experiments using 1,4-dioxane as an organic
co-solvent.
Diselenides 4aec were prepared by the reaction sequence
shown in Scheme 1. Diazotization of ethyl aminobenzoate 1 with
HCl/NaNO2, followed by reaction with KSeCN gave selenocyanate
2.12 Compound 2 was then reduced with LiAlH4 in THF and con-
verted to the dibromomethylphenyl diselenide 3 by heating in an
acetic acid/HBr solution. The final step in the synthetic route was
The vital role of catalyst 4a in the oxidation of NaBr is evident by
comparison of rates in the catalyst-free reaction with rates using
2.5 mol % of 4a, entries 1 and 2, respectively (Table 1). The rate
using 2.5 mol % of catalyst 4a is 130-fold faster than the background
(catalyst-free) reaction. For comparison purposes, the conditions
used in entry 2 were employed as standard conditions. Under
pseudo-first-order conditions (excess H2O2 and NaBr), bromination
of 7 showed first-order dependence for H2O2 (Fig. 1a), with kobs in
a range of 6.99ꢁ10ꢂ5 sꢂ1 to 2.51ꢁ10ꢂ4 sꢂ1 (entries 2e4, Table 1).
With respect to the NaBr concentration, a similar first-order de-
pendence was observed (Fig. 1b) with kobs in the range of
1.04ꢁ10ꢂ4 sꢂ1 to 3.03ꢁ10ꢂ4 sꢂ1 (entries 2, 5 and 6, Table 1).
the reaction of bromide
3 with 1-methylimidazole or 1,2-
dimethylimidazole in THF to furnish the desired catalysts 4aec in
a range of 86e95% yield. Diselenides 4aec are stable compounds
and completely water soluble at the concentrations that we ex-
amined. These compounds were fully characterized by HRMS, 1H
and 13C NMR spectroscopy and showed the characteristic chemical
shift for diselenides in their 77Se NMR spectra (
d z450 ppm).
Scheme 1. Synthetic route for the preparation of catalysts 4aec.
In order to evaluate the ability of diselenides 4aec to activate
H2O2 in aqueous solutions, we studied the oxidation of NaBr. The
formation of ‘Brþ’ can be indirectly measured by the appearance of
brominated products of 4-pentenoic acid (7, Table 1). Bromination
of 7 gives a mixture of 4,5-dibromopentanoic acid (8) and bromo-
lactone 9 under a variety of conditions. Upon standing at pH 6,
dibromide 8 is converted completely to bromolactone 9. The
progress of the reaction can be easily followed by 1H NMR since 7
and 8/9 have distinct 1H NMR signals for the alkene and bro-
moalkane regions.9
Fig. 1. Reaction rate dependence for the bromination of 4-pentenoic 7 acid using
2.5 mol % of 4a on: (a) H2O2 concentration; (b) NaBr concentration.
Catalysts 4b with a 2-methyl substituent on the imidazolium ring,
and 4c, with selenium functionality in the para-position, were also
tested under the standard reaction conditions. Catalyst 4b, krel¼0.98,
displayed essentially the same catalytic activity as 4a (krel¼1.00),
(entries 2 and 7, Table 1). The results with 4b suggest that neither
increased steric interactions from the 2-methyl substituent nor the
enhanced acidity of the hydrogen bonded to the 2-position of the
imidazolium ring, as in catalyst 4a, plays a significant role in the
catalytic process.13 However, the position of the imidazolium ring
relative to the selenium functionality does impact catalytic activity.
The catalytic activity of ortho-substituted catalysts 4a and 4b is ap-
proximately 3-fold higher than that observed for 4c with selenium
functionality in the para-position (entries 2, 7 and 8, Table 1).
The synthetic utility of diselenides as catalysts in oxidation re-
actions arises from its combination with H2O2 to produce seleninic
acids 10 and perseleninic acids 11/12 (Scheme 2). The latter are the
active species in oxidations promoted by the diselenide/H2O2 sys-
tem.3,4,6,9d The question can be asked as to why the imidazolium-
containing catalysts are more active than phenylseleninic acid and
why the ortho-substituted derivatives 12a,b are more active than
para-substituted derivative 12c. The positive charge on the ortho-
substituted imidazolium ring derivatives is positioned to contribute
electrostatically to stabilizing negative charge development in the
perseleninic intermediate 12a,b from diselenides 4a and 4b as
shown in Scheme 2. For the para-substituted derivative 4c, similar
electrostatic stabilization cannot occur intramolecularly in the
seleninic acid/H2O2 intermediate 12c and intermolecular stabiliza-
tion (dimer formation) would be necessary. A previous study for
oxidation of NaBr with H2O2 using selenoxide catalysts demon-
strated increased catalytic activity for selenoxides bearing chelating
amino groups.9e Under the conditions of reaction described in Ref.
9e, selenoxide derivative 13 would be protonated and an electro-
static stabilization of the selenoxide oxygen similar to that described
for 12a,b for the perseleninic acid intermediate would favor addition
of H2O2 to 13 and, thus, would increase catalytic activity. The elec-
tronic structure of the imidazolium group renders it positive at all
times and is consistent with electrostatic contributions to the in-
creased catalytic activity observed with 12a,b.
A kinetic study of the NaBr oxidation was performed by 1H NMR
spectroscopy at 298.1ꢀ0.1 K with pH 6 phosphate buffer solutions
in D2O, 4-pentenoic acid (7, 0.12 M), catalyst 4 (2.5 mol %), H2O2
(0.35e1.4 M) and NaBr (0.64e2.58 M). Rate constants (kobs) and
relative rates (krel) presented in Table 1 are the average of duplicate
runs obtained under conditions where pseudo-first-order behavior
was followed. The 1H NMR signal of H2O/HOD was suppressed and
propionic acid (0.01 M) was used as an internal standard to assess
the conversion of 4-pentenoic acid into products. Diphenyl dis-
elenide 5 was not sufficiently soluble in the aqueous solvent to
Table 1
Bromination of 4-pentenoic acid 7 in aqueous solution promoted by 4aec
c
Entrya Cat pH [H2O2] (mol/L)b [NaBr] (mol/L)b kobs (sꢂ1
)
krel
1
2
3
4
5
6
7
8
9
10
d
6.1 0.7
1.29
1.29
1.29
1.29
0.64
2.58
1.29
1.29
1.29
1.29
(1.07ꢀ0.55)ꢁ10ꢂ6 0.01
(1.44ꢀ0.02)ꢁ10ꢂ4 1.0
(6.99ꢀ0.15)ꢁ10ꢂ5 0.49
(2.51ꢀ0.03)ꢁ10ꢂ4 1.74
(1.04ꢀ0.02)ꢁ10ꢂ4 0.72
(3.03ꢀ0.04)ꢁ10ꢂ4 2.10
(1.41ꢀ0.03)ꢁ10ꢂ4 0.98
(5.27ꢀ0.10)ꢁ10ꢂ5 0.37
(2.49ꢀ0.03)ꢁ10ꢂ4 1.73
(4.30ꢀ0.12) x 10ꢂ6 0.03
4a 6.1 0.7
4a 6.1 0.35
4a 6.1 1.4
4a 6.1 0.7
4a 6.1 0.7
4b 6.1 0.7
4c 6.1 0.7
4a 4.2 0.7
d
4.2 0.7
a
4-Pentenoic acid¼0.12 mol/L (final concentration), catalyst¼2.5 mol % (related
to 4-pentenoic acid).
b
Final concentrations.
c
Average of duplicate runs that agreed within 5% at 298.1ꢀ0.1 K.

10478
E.E. Alberto et al. / Tetrahedron 68 (2012) 10476e10481
Table 2
Optimization of the yield of bromination products for 4-pentenoic acid with 4a,
NaBr and H2O2
a
#
H2O2 (equiv)
Cat (mol %)
Rxn (h)
NaBr (equiv)
Yieldb (%)
7
8
9
1
2
3
4
5
6
7
8
5.0
3.0
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4a/2.5
4a/2.5
4a/2.5
4a/1.0
d
24
24
24
24
24
6
20
20
20
20
20
20
20
20
20
20
20
10
5
0
0
9
8
69
0
0
0
2
3
6
14
8
23
30
11
2
51
61
50
54
7
55
77
55
39
11
1
4a/2.5
4a/2.5
4a/2.5
4a/2.5
5/2.5
6/2.5
4a/2.5
4a/2.5
6c
2c
1c
2c
2c
2c
2c
0
0
Scheme 2. Intermediates in seleninic acid-catalyzed reactions with H2O2.
9
11
59
73
13
29
10
11
12
13
The influence of the pH in the reaction course was another pa-
rameter considered. Using the same concentrations of reagents, the
bromination of 4-pentenoic acid (7) carried out at pH 4.2 (NaH2PO4
0.5 M) is roughly two times faster than that at pH 6.1 (Table 1,
entries 2 and 9). Nevertheless, in the catalyst-free reaction at pH
4.2, negligible bromination of 7 was observed. The catalyzed re-
action is approximately 60 times faster than the catalyst-free re-
action (Table 1, entries 9 and 10, respectively). The role of pH on the
rates of bromination is consistent with the fate of bromine pro-
duced in the aqueous solution. In water, bromine is reversibly hy-
drolyzed to produce hypobromous acid, bromide and 1 equiv of
proton, Scheme 3, Eq. (1).14 Under acidic conditions, the equilib-
rium is shifted to the formation of bromine. On the other hand, if
HOBr is predominant in the equilibrium and H2O2 is present, the
reaction that can take place is the irreversible disproportionation of
H2O2, producing singlet oxygen, bromide and a proton, as shown in
Eq. (2).15 In other words, the ‘Brþ’ produced in the media (HOBr, Br2
or Brꢂ3 ) can be competitively quenched by H2O2 or react with
substrate to produce product, as shown in Eq. (3).
14
9
45
41
a
Reaction at room temperature; solvent¼20 mL of aqueous 0.5 M NaH2PO4 (pH
4.2); [4-pentenoic acid (7)¼0.075 mol/L].
b
Yield determined by 1H NMR spectroscopic analysis of the extracted mass (ethyl
acetate, 4ꢁ8 mL) followed by addition of 0.5 g of NaHSO3 to the organic layer. The
organic phase was then washed with brine (1ꢁ10 mL), dried with MgSO4, filtered,
and solvent removed.
c
Solvent¼20 mL of a 3/1 mixture of NaH2PO4 0.5 M in water (pH 4.2) and 1,4-
dioxane.
The apparent inconsistency of the results using different
amounts of H2O2 was elucidated in another set of experiments. The
kinetics experiments showed a linear relationship between the
increase of the peroxide concentration and consumption of 4-
pentenoic acid over the initial half-life of reaction, where condi-
tions remain pseudo-first-order. The preparative reactions under
the conditions of Table 2, while initially pseudo-first-order, will
become higher order as H2O2 is consumed and rates of reaction will
slow. The data in Table 2 also indicate that the use of 3 equiv of H2O2
instead of 5 gives a higher yield of brominated products. We rea-
soned that this discrepancy may be actually due to the hydrolysis of
the final product, so an experiment was performed using a shorter
reaction time (6 vs 24 h). The amount of isolated brominated
products increased by 8%, full consumption of 7 was observed along
with 4,5-dibromopentanoic acid 8 (14%) and lactone 9 (55%) (Table
2, entry 2 vs entry 6).
1,4-Dioxane was found to be an effective co-solvent with pH 4.2
phosphate buffer in entries 7e13 of Table 2. The reactions were
homogeneous and products could be readily extracted from the 3/1
buffer/dioxane solvent. With catalyst 4a, the buffer/dioxane solvent
increased the yield of brominated products to 85% with bromo-
lactone 9 as the major product (Table 2, entry 7). Shorter reaction
times with this solvent system gave different distribution of
products, and clearly showed that the full conversion of starting
material to the brominated products occurs between 1 h and 2 h of
reaction (entries 8 and 9).
Diphenyl diselenide 5, which was soluble in the 3/1 buffer/di-
oxane solvent, was a poorer catalyst compared to the diselenide 4a
under the conditions described in Table 2. While catalyst 4a pro-
moted complete bromination of 7 within 2 h (ꢃ5 half-lives) with
brominated products isolated in 78% yield, PhSeSePh (5) gave only
22% bromination of 4-pentenoic acid with 59% 4-pentenoic acid (7)
remaining (<1 half-life, Table 2, entries 8 and 10, respectively).
Brominated products 8 and 9 were observed in only 11% yield by 1H
NMR spectroscopy using PhSeSePh (5) as catalyst. Ionic liquid 6
lacking the diselenide functionality gave only trace amounts of
brominated products 8 and 9 as observed by 1H NMR spectroscopy
(entry 11).
Scheme 3. Reaction sequences for the hydrolysis of Br2 or H2O2 disproportionation
promoted by HOBr.
We next examined a series of preparative experiments [1.5 mmol
of 4-pentenoic acid (7)] in order to optimize the formation of the
brominated products 8/9 using a NaBr/H2O2 mixture catalyzed by 4a
(Table 2). Considering that, ideally, the reaction should be acidic and
have a lower concentration of H2O2 to minimize the unproductive
disproportionation of H2O2, further experiments were conducted at
pH 4.2. Initially the number of equivalents of H2O2 required to ac-
complish the bromination of 4-pentenoic acid (7) was evaluated in
reactions conducted for 24 h at ambient temperature. The compo-
sition of the reaction mixture was analyzed by 1H NMR spectroscopy
following extraction of products with ethyl acetate and quenching
the remaining peroxide with a sodium bisulfite wash. As indicated in
Table 2 the reaction with 3 equiv of H2O2 and 2.5 mol % of catalyst 4a
gave the best results, with complete consumption of 7 after 24 h and
bromolactone 9 as the only observable product (by 1H NMR spec-
troscopy), which was recovered in a yield of 61% (entry 2). Reactions
carried out with 5 equiv of H2O2 produced 51% of the same product,
while 1.5 equiv were not sufficient to give complete conversion of 4-
pentenoic acid (7) to products (Table 2, entries 1 and 3, respectively).
Incomplete bromination of 7 was also observed employing 1.0 mol %
of catalyst or in a catalyst-free reaction (entries 4 and 5, respectively).
Lowering the amount of NaBr also reduced the yield of bromi-
nated products 8 and 9 in the 4a-catalyzed reactions. With 10 and
20 equiv of NaBr, 4-pentenoic acid (7) was observed as 13% and 29%

E.E. Alberto et al. / Tetrahedron 68 (2012) 10476e10481
10479
of the reaction mixture, respectively (entries 12 and 13, re-
spectively, Table 2).
were efficiently brominated using lower quantities (1.1e1.5 equiv)
of H2O2 under the standard conditions. Negligible product forma-
tion was observed in the catalyst-free experiments (entries 5e7).
The results from a series of preparative bromination reactions
(1.5 mmol in substrate) with 4-pentenoic acid, 5-hexenoic acid,
E-3-hexenoic acid, 1,3,5-trimethoxybenzene, and N-phenyl-
morpholine as substrates are summarized in Table 3. These
substrates were chosen primarily due to their commercial
availability. The reactions were run using 2.5 mol % of diselenide
4a as catalyst and 3/1 pH 4.2 phosphate buffer/1,4-dioxane as
solvent.
3. Conclusions
In this study we describe the synthesis of novel, water-soluble
diselenides 4aec, which are efficient catalysts for the oxidation of
NaBr with H2O2 in aqueous solutions. The N-methylimidazolium
group in these compounds imparts the water solubility, a charac-
Table 3
Representative substrates brominated using NaBr/H2O2 with 2.5 mol % of 4a in a 3/1 mixture of pH 4.2 phosphate buffer/dioxane
a
#
1
Substrate
H2O2 (equiv)
Time (h)
Product
Yieldb (%)
Catalyst-free (%)c
4
3
7
82ꢀ3
2d
3d
4
3
3
3
2.5
7
68ꢀ2
65ꢀ4
79ꢀ2
1
n.d.
2
7
5
6
1.1
4.5
94ꢀ2
3
1.1
1.5
4.5
4.5
71
n.d.
2
7
87ꢀ4
a
Substrate¼1.5 mmol; H2O2 (8.8 M) using the amounts indicated in the table; NaBr 30 mmol (20 equiv); catalyst 4a 2.5 mol % (related to substrate); solvent¼20 mL of a 3/1
mixture of NaH2PO4 0.5 M in water (pH 4.2) and 1,4-dioxane; room temperature.
b
Average isolated yields of duplicate reactions.
c
Yields from 1H NMR spectroscopy.
d
Along with approximately 4% of six-membered lactone.
On the 1.5-mmol scale, 4-pentenoic acid 7 gave bromolactone 9
in 82% isolated yield after 7 h of reaction, while only 4% of the same
product was observed in the catalyst-free reaction (Table 3, entry
1). Bromination of 7 was also conducted on a 20-mmol scale in pH
4.2 phosphate buffer (200 mL) and 1,4-dioxane (70 mL) using
2.5 mol % of diselenide 4a as catalyst, 20 equiv of NaBr and 3 equiv
of H2O2. After 7 h of reaction at ambient temperature, bromo-
lactone 9 was extracted from the aqueous phase with ethyl acetate
in 2.65 g (74%) yield. Bromination of 5-hexenoic acid 13 gave 5,6-
dibromohexanoic acid (14, 68% yield) as the major product after
2.5 h of reaction (Table 3, entry 2). A longer reaction time (7 h) did
not improve this result (entry 3). In both cases, approximately 4% of
the corresponding six-membered bromolactone was formed. With
this substrate, the catalyst-free reaction gave only trace amounts of
brominated products (ꢄ1%). Bromination of E-3-hexenoic acid 15
followed by elimination of HBr furnished 5-ethyl-2-furanone 16 in
79% yield (entry 4). With this substrate, the uncatalyzed reaction
gave ꢄ2% of the same product. The electron rich aromatic com-
pounds 1,3,5-trimethoxybenzene 17 and 4-phenylmorpholine 19
teristic uncommon in ordinary organic diselenides. The formation
of ‘Brþ’ species was monitored by 1H NMR spectroscopy in D2O,
through the reaction of ‘Brþ’ with 4-pentenoic acid. Kinetics ex-
periments revealed that the reaction for the oxidation of NaBr
with H2O2 is first-order dependent in both NaBr and H2O2 and is
also sensitive to the pH of the reaction medium. The catalytic
performance of 4aec is impacted by the proximity of the imid-
azole group to the selenium functionality. With 4a and 4b, the
imidazole group is in the ortho-position and these two com-
pounds showed nearly identical catalytic activity. In contrast, 4c
with the imidazole group in the para-position relative to the se-
lenium functionality was approximately 3-fold less active. These
data suggest that electrostatic interactions are perhaps important
in stabilizing the seleninic acid/H2O2 intermediate. Diphenyl dis-
elenide was a very poor catalyst for bromination with H2O2/NaBr
and the ionic liquid 1-benzyl-3-methylimidazolium bromide 6
showed no catalytic activity for the same transformation. An ob-
vious synergy is apparent from the linking of the two different
functional groups.

10480
E.E. Alberto et al. / Tetrahedron 68 (2012) 10476e10481
Bromination of organic substrates was observed in all-aqueous
MgSO4, filtered through CeliteÒ, and concentrated. The crude
product, 3a or 3b, was used in the next reaction without further
purification.
solutions using 4a as a catalyst for H2O2 activation. However, im-
proved results were obtained employing 3/1 mixtures of 0.5 M
NaH2PO4 (pH 4.2) and 1,4-dioxane as an organic co-solvent. The use
of 2.5 mol % of 4a allowed bromination of suitable substrates
employing the NaBr/H2O2 system in high yields as shown in Table 3.
In contrast, catalyst-free systems gave negligible formation of
products in control experiments. Bromination of 4-pentenoic acid
was also successfully performed on a multi-gram scale. Other
synthetic applications for the activation of H2O2 by 4aec are cur-
rently under investigation.
4.1.2.1. 1,2-Bis(2-(bromomethyl)phenyl)diselenide (3a).12 Brown-
ish-orange solid, mp 71e73 ꢅC; Yield: 82%; 1H NMR (CDCl3,
500 MHz):
d
¼7.72 (d, J¼8.0 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H), 7.26 (t,
J¼7.5 Hz, 1H), 7.21 (t, J¼7.5 Hz, 1H), 4.59 (s, 2H); 13C NMR (CDCl3,
75 MHz):
d
¼139.22, 135.41, 132.47, 130.08, 129.66, 128.98, 33.85,
HRMS, m/z 497.7635 (calcd for C14H12Br280Se2 497.7636).
4.1.2.2. 1,2-Bis(4-(bromomethyl)phenyl)diselenide (3b). Yellow
4. Experimental section
4.1. General
solid, mp 84e85 ꢅC; Yield 91%; 1H NMR (CDCl3, 500 MHz):
d
¼7.49
(d, J¼7.5 Hz, 2H), 7.21 (d, J¼8.5 Hz, 2H), 4.38 (s, 2H); 13C NMR
(CDCl3, 75 MHz):
d
¼137.35,131.52,130.97,129.80, 32.76; HRMS, m/z
497.7635 (calcd for C14H12Br280Se2 497.7636).
1H, 13C and 77Se NMR spectra were recorded at 500, 75 and
76 MHz, respectively, with tetramethylsilane as internal standard
for 1H and 13C spectra and diphenylselenide as internal standard for
77Se NMR spectra. All other solvents and chemicals were used as
purchased unless otherwise noted.
4.1.3. Procedure for the synthesis of 4aec. 1-Methylimidazole
(0.95 mL, 11 mmol) or 1,2-dimethylimidazole (0.98 mL, 11 mmol)
was added to a solution of 3a or 3b (2.49 g, 5 mmol) in THF (5 mL)
and the resulting solution was stirred at ambient temperature.
Within 20 min of the addition of the imidazole, the formation of
a yellow solid could be observed. After 4 h, Et2O (10 mL) was added
and the resulting mixture stirred for an additional 10 min. The
solids in the reaction mixture were allowed to settle and the or-
ganic layer was decanted. Another 10 mL of Et2O was added, the
mixture stirred for 10 min, allowed to settle and decanted. This
procedure was repeated a total of three times. Finally, the product
(yellow solid) was dried under vacuum overnight and kept under
argon.
4.1.1. Procedure for the synthesis of 2aeb.12 A mixture of ethyl
aminobenzoate 1a or 1b (3.3 g, 20 mmol) and NaBF4 (3.3 g,
30 mmol) was suspended in 2 N HCl (30 mL) at 0 ꢅC. Then a solu-
tion of NaNO2 (1.45 g, 21 mmol, dissolved in 20 mL of water) was
added dropwise while the mixture was held at 0 ꢅC. After stirring
for 1 h, saturated sodium acetate (ca. 40 mL) was added dropwise
until the mixture reached pH 6. Then, the mixture was poured in
one portion into an aqueous solution of KSeCN (2.88 g, 20 mmol,
dissolved in 40 mL of water). The reaction mixture was stirred 1 h
at ambient temperature and then extracted with Et2O (3ꢁ30 mL).
The combined ether extracts were dried over MgSO4 and concen-
trated. Purification was performed via column chromatography on
flash silica, eluting with a 20/80 (v/v) mixture of ethyl acetate/
hexanes.
4.1.3.1. Diselenide (4a). Yellow solid (hygroscopic), yield 94%; 1H
NMR (D2O, 500 MHz):
7.27e7.24 (m, 1H), 7.20 (s, 1H); 5.30 (s, 2H), 3.75 (s, 3H); 13C NMR
(D2O, 125 MHz):
¼137.87, 136.11, 135.42, 131.36, 131.04, 130.80,
d
¼8.58 (s,1H), 7.43e7.38 (m, 3H), 7.31 (s,1H),
d
130.63, 123.70, 122.09, 52.89, 35.86; 77Se NMR (D2O, 76 MHz):
d
¼454.87; HRMS, m/2z 252.0160 (calcd for ½C14H24N480Se2ꢆ2þ
4.1.1.1. Ethyl 2-selenocyanatobenzoate (2a). Pale yellow solid,
252.0160).
mp 122e124 ꢅC; Yield 85%; 1H NMR (CDCl3, 500 MHz):
d
¼8.13 (d,
J¼8.0 Hz, 1H), 8.06 (d, J¼9.0 Hz, 1H), 7.60 (t, J¼7.0 Hz, 1H), 7.43 (t,
4.1.3.2. Diselenide (4b). Yellow solid (hygroscopic), yield 86%;
1H NMR (D2O, 500 MHz):
J¼7.5 Hz, 1H), 4.44 (q, J¼6.8 Hz, 2H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR
d
¼7.48 (d, J¼7.5 Hz, 1H), 7.36 (t, J¼7.0 Hz,
(CDCl3, 75 MHz):
d
¼167.85, 134.48, 131.28, 131.09, 129.93, 127.49,
1H), 7.22 (t, J¼7.5 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J¼7.5 Hz, 1H), 6.87 (s,
126.44, 105.81, 62.63, 14.12; HRMS, m/z 254.9804 (calcd for
1H), 5.11 (s, 2H), 3.63 (s, 3H), 2.36 (s, 3H); 13C NMR (D2O, 125 MHz):
C10H9NO280Se 254.9799).
d
¼144.51, 137.91, 135.60, 130.84, 130.68, 130.28, 129.74, 122.44,
120.54, 51.63, 34.82, 9.41; 77Se NMR (D2O, 76 MHz):
d
¼458.65;
4.1.1.2. Ethyl 4-selenocyanatobenzoate (2b). Yellow solid, mp
HRMS, m/z 610.9822 (calcd for ½C24H28BrN480Se2ꢆþ 610.9822).
112e114 ꢅC; Yield 66%; 1H NMR (CDCl3, 500 MHz):
d¼8.06 (d,
J¼8.5 Hz, 2H), 7.67 (d, J¼8.5 Hz, 2H), 4.40 (q, J¼7.0 Hz, 2H), 1.41 (t,
4.1.3.3. Diselenide (4c). Yield 95%; 1H NMR (CD3OD, 500 MHz):
J¼7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d
¼165.27, 131.35, 131.22,
d
¼8.90 (s, 1H), 7.62 (d, J¼8.5 Hz, 2H), 7.55 (s, 1H), 7.54 (s, 1H), 7.32
131.12, 127.80, 100.39, 61.39, 14.15; HRMS, m/z 254.9796 (calcd for
(d, J¼8.5 Hz, 2H), 5.37 (s, 2H), 3.90 (s, 3H); 13C NMR (D2O,125 MHz):
C10H9NO280Se 254.9799).
d
¼135.83, 133.38, 131.57, 131.38, 129.57, 123.85, 121.95, 51.99, 35.79;
77Se NMR (D2O, 76 MHz):
d¼451.41; HRMS, m/z 582.9515 (calcd for
4.1.2. Procedure for the synthesis of 3aeb.12 LiAlH4 (285 mg,
7.5 mmol) was suspended in anhydrous Et2O (60 mL) under an
argon atmosphere and 2a or 2b (1.27 g, 5 mmol, dissolved in 40 mL
of Et2O) was slowly added to the mixture. After heating at reflux for
2 h, the reaction mixture was cooled with an ice bath, 2 N HCl (ca.
25 mL) was carefully added and the mixture was stirred under air
overnight. The organic layer was separated, washed with water,
dried over MgSO4, and concentrated. The crude alcohol was dried
under vacuum for 2 h and acetic acid (25 mL) was added, followed
by the slow addition of 48% hydrobromic acid (17 mL). The resulting
mixture was heated at 90 ꢅC for 3.5 h and then cooled to ambient
temperature. Aqueous Na2CO3 was added to neutralize the reaction
mixture, which was then extracted with Et2O (3ꢁ20 mL). The
combined organic extracts were washed with brine, dried over
½C22H24BrN480Se2ꢆþ 582.9509).
4.2. Procedure for the synthesis of 1-benzyl-3-
methylimidazolium bromide (6).16
1-Methylimidazole (1.6 mL, 20 mmol) was added to a solution of
benzyl bromide (3.49 g, 20 mmol) dissolved in THF (20 mL). The
mixture was stirred at ambient temperature overnight and the
solvent removed furnishing a viscous oil. This oil was washed with
Et2O (3ꢁ10 mL) and dried under vacuum. The final product is a pale
yellow oil, yield 86%; 1H NMR (CD3OD, 500 MHz):
d
¼9.07 (s, 1H),
7.62 (t, J¼2.0 Hz, 1H), 7.59 (t, J¼2.0 Hz, 1H), 7.46e7.40 (m, 5H), 5.44
(s, 2H), 3.94 (s, 3H); 13C NMR (CD3OD, 75 MHz):
130.20, 129.80, 125.11, 123.45, 53.82, 36.85.
d¼135.33, 130.27,

E.E. Alberto et al. / Tetrahedron 68 (2012) 10476e10481
10481
Kinetic studies: all the solutions used for these experiments were
prepared in D2O. The progress of the reaction was monitored by 1H
NMR spectroscopy at 298ꢀ0.1 K suppressing the signal corre-
sponding to the H2O/HOD signal. Different stock solutions were
prepared in pH 6.1 phosphate buffer (Na2HPO4, 0.25 M) or pH 4.2
(NaH2PO4 0.5 M) containing 4-pentenoic acid (7, 0.15 M), propionic
acid (0.010 M), and NaBr (0.825 M, 1.65 M or 3.3 M). Serial dilution
of H2O2 was employed to prepare 4.4 M and 2.2 M solutions from
commercially available 8.8 M H2O2. Catalysts 4aec were dissolved
in D2O to produce 0.05 M solutions. One milliliter of the stock so-
lution was transferred to a vial (0.15 mmol of 7 along with the
J¼11.5 Hz, 2H), 3.83 (t, J¼6.5 Hz, 4H), 3.10 (t, J¼6.0 Hz, 4H); 13C NMR
(CDCl3, 100 MHz):
d
¼150.20, 131.84, 117.17, 112.02, 66.65, 49.00.
Acknowledgements
E.E.A. and M.R.D. thank the Office of Naval Research (U.S.A.) for
support of this work (award N0014-09-1-0217). E.E.A. is obliged to
CNPq for a Sandwich PhD Fellowship Grant (award 200334/2009-
ꢀ
3). A.L.B. thanks CNPq (INCT-Catalise) for financial support. Dr.
Dinesh Sukumaran and Bharathwaj Sathyamoorthy (SUNY at Buf-
falo) are acknowledged for their help in the NMR experiments.
corresponding amount of NaBr), followed by the addition of 75
of the stock solution of catalyst 4aec (0.00375 mmol, 2.5 mol %)
and 205 L of the desired H2O2 solution. The mixture was quickly
mL
References and notes
m
transferred to a 5-mm NMR tube and acquisitions were recorded at
300-s intervals with the total time of the experiment being ap-
proximately 90 min. The consumption of 4-pentenoic acid was
measured comparing the changes between the relative integral
values of the internal alkene proton of 4-pentenoic acid
1. (a) Kleemann, A.; Engel, J. In Pharmaceutical Substances, 4th ed.; Thieme: New
York, NY, 2001; (b) Dagani, M. J.; Barda, H. J.; Benya, T. J.; Sanders, D. C. In
Ullmann’s Encyclopedia of Industrial Chemistry: Bromine Compounds; Wiley-VCH:
Weinheim, 2002; (c) De Meijere, A.; Diederich, F. In Metal-catalyzed Cross-
coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004.
2. (a) Eissen, M.; Lenoir, D. Chem.dEur. J. 2008, 14, 9830e9841; (b) Podgorsek, A.;
Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron 2009, 65, 4429e4439; (c) Podgorsek,
A.; Zupan, M.; Iskra, J. Angew. Chem., Int. Ed. 2009, 48, 8424e8450 and cited
references.
3. (a) Hori, T.; Sharpless, K. B. J. Org. Chem. 1978, 43, 1689e1697; (b) Reich, H. J.;
Chow, F.; Peake, S. L. Synthesis 1978, 299e301; (c) Brink, G. J.; Fernandes, B. C.
M.; Vliet, M. C. A.; Arends, I. W. C. E.; Sheldon, R. A. J. Chem. Soc., Perkin Trans. 1
2001, 224e228; (d) Mercier, E. A.; Smith, C. D.; Parvez, M.; Back, T. G. J. Org.
Chem. 2012, 77, 3508e3517.
(
d
¼5.8 ppm) and the methylene protons of propionic acid
(d
¼1.1 ppm). The results were plotted following pseudo-first-order
conditions (time in seconds vs ln [4-pentenoic acid]).
4.3. General procedure for bromination of organic substrates
4. Brink, G. J.; Vis, J. M.; Arends, I. W. C. E.; Sheldon, R. A. J. Org. Chem. 2001, 66,
2429e2433.
1,4-Dioxane (5 mL) was added to a mixture of substrate
(1.5 mmol) and NaBr (3.09 g, 30 mmol). Catalyst 4a, 2.5 mol %
(25 mg, 0.0375 mmol) was dissolved in 15 mL of a pH 4.2 phos-
phate solution (NaH2PO4 0.5 M) and added to the reaction mixture.
Then, H2O2 (8.8 M) was added (the number of equivalents of H2O2
is described in Table 3) and the reaction stirred at room tempera-
ture for the amount of time reported in Table 3. The products were
extracted with ethyl acetate (4ꢁ8 mL), the combined organic ex-
tracts were washed with 20 mL of NaHSO3 0.5 M, 20 mL of brine,
dried over MgSO4, and concentrated under vacuum. When re-
quired, purification was performed by column chromatography on
flash silica.
5. (a) Mugesh, G.; Mont, W. W.; Sies, H. Chem. Rev. 2001, 101, 2125e2179; (b)
Malmstrom, J.; Jonsson, M.; Cotgreave, I. A.; Hammarstrom, L.; Sjodin, M.;
Engman, L. J. Am. Chem. Soc. 2001, 123, 3434e3440; (c) Back, T. G.; Moussa, Z. J.
Am. Chem. Soc. 2003, 125, 13455e13460; (d) Back, T. G.; Moussa, Z.; Parvez, M.
Angew. Chem., Int. Ed. 2004, 43 1268e1270; (e) Nogueira, C. W.; Zeni, G.; Rocha,
J. B. T. Chem. Rev. 2004, 104, 6255e6285; (f) Kumar, S.; Johansson, H.; Kanda, T.;
Engman, L.; Muller, T.; Jonsson, M.; Pedulli, G. F.; Petrucci, S.; Valgimigli, L. Org.
Lett. 2008, 10, 4895e4898; (g) Alberto, E. E.; Soares, L. C.; Sudati, J. H.; Borges,
A. C. A.; Rocha, J. B. T.; Braga, A. L. Eur. J. Org. Chem. 2009, 4211e4214; (h) Al-
berto, E. E.; Nascimento, V.; Braga, A. L. J. Braz. Chem. Soc. 2010, 21, 2032e2041;
(i) Kumar, S.; Johansson, H.; Kanda, T.; Engman, L.; Muller, T.; Bergenudd, H.;
Jonsson, M.; Pedulli, G. F.; Amorati, R.; Valgimigli, L. J. Org. Chem. 2010, 75,
716e725.
ꢀ
6. (a) Mlochowski, J.; Brzaszcz, M.; Giurg, M.; Palus, J.; Wojtowicz, H. Eur. J. Org.
Chem. 2003, 4329e4339; (b) Alberto, E. E.; Braga, A. L. In Selenium and Tellurium
Chemistry - From Small Molecules to Biomolecules and Materials; Springer: Ber-
lin, 2011; 251e283.
7. Leonard, K. A.; Zhou, F.; Detty, M. R. Organometallics 1996, 15, 4285e4292.
8. (a) Wang, C.; Tunge, J. A. Chem. Commun. 2004, 2694e2695; (b) Mellegaard, S.
R.; Tunge, J. A. J. Org. Chem. 2004, 69, 8979e8981; (c) Tunge, J. A.; Mellegaard,
S. R. Org. Lett. 2004, 6, 1205e1207; (d) Mellegaard-Waetzig, S. R.; Wang, C.;
Tunge, J. A. Tetrahedron 2006, 62, 7191e7198.
9. (a) Francavilla, C.; Bright, F. V.; Detty, M. R. Org. Lett. 1999, 1, 1043e1046; (b)
Francavilla, C.; Drake, M. D.; Bright, F. V.; Detty, M. R. J. Am. Chem. Soc. 2001, 123,
57e67; (c) Drake, M. D.; Bright, F. V.; Detty, M. R. J. Am. Chem. Soc. 2003, 125,
12558e12566; (d) Drake, M. D.; Bateman, M. A.; Detty, M. R. Organometallics
2003, 22, 4158e4162; (e) Goodman, M. A.; Detty, M. R. Organometallics 2004,
23, 3016e3020; (f) Bennett, S. M.; Tang, Y.; McMaster, D.; Bright, F. V.; Detty, M.
R. J. Org. Chem. 2008, 73, 6849e6852.
10. For recent reviews about the use of organoselenium compounds in a green
context see: (a) Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J. Org. Chem.
2009, 1649e1664; (b) Freudendahl, D. M.; Santoro, S.; Shahzad, S. A.; Santi, C.;
Wirth, T. Angew. Chem., Int. Ed. 2009, 48, 8409e8411.
11. (a) You, Y.; Ahsan, K.; Detty, M. R. J. Am. Chem. Soc. 2003, 125, 4918e4927; (b)
Goodman, M. A.; Detty, M. R. Synlett 2006, 1100e1104; (c) Braga, A. L.; Alberto,
E. E.; Soares, L. C.; Rocha, J. B. T.; Sudati, J. H.; Roos, D. H. Org. Biomol. Chem.
2009, 7, 43e45; (d) Nascimento, V.; Alberto, E. E.; Tondo, D. W.; Dambrowski,
D.; Detty, M. R.; Nome, F.; Braga, A. L. J. Am. Chem. Soc. 2012, 134, 138e141.
12. (a) Iwaoka, M.; Tomoda, S. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 67,
125e130; (b) Iwaoka, M.; Katsuda, T.; Komatsu, H.; Tomoda, S. J. Org. Chem.
2005, 70, 321e327.
13. Handy, S. T.; Okello, M. J. Org. Chem. 2005, 70, 1915e1918.
14. Espenson, J. H.; Pestovsky, O.; Huston, P.; Staudt, S. J. Am. Chem. Soc. 1994, 116,
2869e2877.
15. (a) Everett, R. R.; Butler, A. Inorg. Chem. 1989, 28, 393e395; (b) Everett, R. R.;
Kanofskyen, J. R.; Butler, A. J. Biol. Chem. 1990, 265, 4908e4914.
16. Harjani, J. R.; Farrell, J.; Garcia, M. T.; Singer, R. D.; Scammells, P. J. Green Chem.
2009, 11, 821e829.
4.3.1. 5-(Bromomethyl)dihydrofuran-2(3H)-one (9)9f (Table 3, entry
1). Yield 82%; 1H NMR (CDCl3, 500 MHz):
d
¼4.78e4.73 (m, 1H),
3.60e3.53 (m, 2H), 2.70e2.54 (m, 2H), 2.49e2.42 (m, 1H),
2.17e2.09 (m, 1H); 13C NMR (CDCl3, 75 MHz):
d¼176.10, 77.77,
34.07, 28.27, 26.07.
4.3.2. 5,6-Dibromohexanoic acid (14) (Table 3, entry 2). Yield 68%;
1H NMR (CDCl3, 500 MHz):
d
¼11.68 (br, 1H), 4.19e4.15 (m, 1H),
3.88e3.85 (m, 1H), 3.63 (t, J¼10.0 Hz, 1H), 2.48e2.40 (m, 2H),
2.26e2.20 (m, 1H), 2.00e1.92 (m, 1H), 1.89e1.73 (m, 2H); 13C NMR
(CDCl3, 75 MHz):
d
¼179.40, 51.91, 35.90, 35.23, 33.12, 22.03; HRMS
m/z calcd for [C6H9Br2O]þ 254.9015, found 254.9015.
4.3.3. 5-Ethylfuran-2(5H)-one (16)17 (Table 3, entry 3). Yield 79%;
1H NMR (CDCl3, 500 MHz):
d
¼7.47 (d, J¼5.5 Hz, 1H), 6.12 (d,
J¼5.5 Hz, 1H), 5.02 (t, J¼5.5 Hz, 1H), 1.88e1.83 (m, 1H), 1.77e1.71
(m, 1H), 1.02 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
¼173.15,
d
156.08, 121.64, 84.25, 26.22, 8.94.
4.3.4. 2-Bromo-1,3,5-trimethoxybenzene (18)9f (Table 3, entry
4). Yield 94%; 1H NMR (CDCl3, 500 MHz):
6H), 3.81 (s, 3H); 13C NMR (CDCl3, 75 MHz):
91.59, 56.24, 55.42.
d
¼6.16 (s, 2H), 3.87 (s,
d
¼160.36,157.34, 91.83,
4.3.5. N-(4-Bromophenyl)morpholine (20)9f (Table 3, entry 5). Yield
87%; 1H NMR (CDCl3, 400 MHz):
¼7.34 (d, J¼9.0 Hz, 2H), 6.75 (d,
17. Fujita, K.; Hashimoto, S.; Kanakubo, M.; Oishia, A.; Taguchi, Y. Green Chem. 2003,
5, 549e553.
d