A novel tunable aromatic bromination method using alkyl bromides and sodium hydride in DMSO

Article abstract of DOI:10.1016/j.tetlet.2006.03.191

Aromatic bromination on various aromatic systems with different substitutions was performed in the presence of alkyl bromide and sodium hydride in DMSO. Mono-bromination on a wide range of substrates was achieved by selecting proper alkyl bromides and controlling its amount. Further bromination could happen with more active alkyl bromides and additional amount of bromides and sodium hydride. The yields ranged from moderate to excellent. In addition, reaction mechanism was postulated to explain our observations.

Full text of DOI:10.1016/j.tetlet.2006.03.191

Tetrahedron Letters 47 (2006) 3889–3892
A novel tunable aromatic bromination method using alkyl
bromides and sodium hydride in DMSO
MaoJun Guo,* Laszlo Varady, Demosthenes Fokas, Carmen Baldino and Libing Yu
ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 26 January 2006; accepted 29 March 2006
Available online 27 April 2006
Abstract—Aromatic bromination on various aromatic systems with different substitutions was performed in the presence of alkyl
bromide and sodium hydride in DMSO. Mono-bromination on a wide range of substrates was achieved by selecting proper alkyl
bromides and controlling its amount. Further bromination could happen with more active alkyl bromides and additional amount of
bromides and sodium hydride. The yields ranged from moderate to excellent. In addition, reaction mechanism was postulated to
explain our observations.
Ó 2006 Elsevier Ltd. All rights reserved.
Bromoarenes continue to be important synthetic inter-
mediates for pharmaceutical and or other chemical
related industries. The Suzuki coupling reaction1 using
bromoarenes as starting materials has fueled the devel-
opment of efficient and selective bromination under
milder conditions.2–4 A variety of electrophilic bromina-
tion reagents include NBS/HBF4–Et2O, Br2 in haloge-
nated hydrocarbons or acetic acid, dioxane dibromide,
pyridinum hydrobromide perbromide, DBU hydro-
bromide, tetra-alkyl ammonium tribromide, and bromo-
dimethylsulfonium bromide [(CH3)2SBr2],5 which have
been of choice for different substrates.6 Herein, we
wish to report a novel tunable aromatic bromination
method for diverse set of substrates under basic condi-
tions, using alkyl bromides and sodium hydride in
DMSO.7
allyl chloride, allyl bromide, allyl iodide, 1-chloro-2-
pentyne, and 1-bromo-2-pentyne, for the development
of screening libraries. Besides alkylating reaction, an
unexpected bromination reaction occurred to produce
brominated by-products (compounds 3, 4, and 5) when
the reaction was run in DMSO at 80 °C with excess of
alkyl bromide and nonnucleophilic base sodium
hydride9 (Scheme 1). The distribution of brominated
products (3, 4, and 5) varied with different alkyl
bromides used. However, chlorination or iodination
did not occurred under the same reaction condition,
while alkyl chlorides or alkyl iodides were used in place
of bromide correspondingly.
It is noteworthy that Fletcher and Fan10 reported the
bromination of anilines in the presence of ethyl bromide
in DMSO, but it required a much higher temperature
(150 °C). In our case, bromination was observed only
when DMSO was used as solvent and sodium hydride
was used as base. Other bases, such as t-ButOK, did
This bromination system was initially discovered in the
course of investigating alkylating reaction of dihydro-
quinazolin-4-one 18 with various alkyl halides including
Br
H
N
R1
H
N
R1
H
N
H
N
R1
N
R1
R1
N
H
N
NaH / 2 eq.RBr
DMSO
R2
R2
R2
R2
R2
+
NH
+
NH
+
NH
80ºC
Br
Br
Br
O
O
O
O
O
R
R
3
5
2
4
1
Scheme 1. Bromination of dihydroquinazolin-4-ones (1) with different alkyl bromides.
*
Corresponding author. E-mail: MaoGuo2001@yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.191

3890
M. Guo et al. / Tetrahedron Letters 47 (2006) 3889–3892
Table 1. Unexpected formation of brominated products (percentage of components as determined by LC–MS using ELSD)
Entry
RX
Solvent/base
2
3
4
5
1
2
3
4
5
6
7
8
9
CH2@CHCH2Cl
CH2@CHCH2I
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH3CH2Br
DMSO/NaH
DMSO/NaH
DMF/NaH
54
8
—
—
—
—
—
8
37
21
5
—
—
—
—
—
77
49
57
48
18
8
—
—
—
—
—
85
15
50
—
—
—
6
DMSO/t-BuOK
THF/t-BuOK
DMSO/NaH
DMSO/NaH
DMSO/NaH
DMSO/NaH
DMSO/NaH
DMSO/NaH
—
—
—
10
—
PhCH2Br
CH3CH2C„CCH2Br
CH3OCOCH2Br
CH3CH2COCH2Br
10
11
—
—
—
—
not induce bromination. Replacement of DMSO with
DMF shut down the bromination as well. The results
are summarized in Table 1.
matic compounds with different reactivity toward
bromination.
Firstly, 2-bromopentane was selected for bromination of
other aromatic compounds. While phenyl, naphthanyl,
and indolyl aromatic systems with electron rich directing
substituents, such as amino groups and alkoxyl groups
gave clean mono-brominated product, with regioselec-
tivity and good to quantitative yields, as shown in Fig-
ure 1, attempts of bromination on alkyl, mono-alkoxyl
substituted benzene, acetophenones, pyridine, pyrrole,
and furan did not give controlled brominating products.
Generally, nonactivated substrates with deficient elec-
tron density did not work under this set of condition.
The effect of alkyl bromides on the selectivity of bromin-
ation over alkylation was further investigated. Seven
alkyl bromides representing a wide range of molecular
weights, steric and electronic properties were selected.
The reaction mixture was analyzed by LC–MS after
16 h at 80 °C, and the results are summarized in Table 2.
It is shown in Table 2 that secondary alkyl bromides in
entries 2–8 eliminated the formation of alkylated prod-
ucts (2, 3) due to increased steric hindrance in compari-
son to primary alkyl bromide in entry 1. In fact, mono-
brominated product 4 was formed exclusively in entries
2–4. Furthermore, introduction of ester group next to
bromides resulted in di-bromination along with mono-
bromination in entries 5 and 6. This indicated that elec-
tron withdrawing functionality increased the brominat-
ing reactivity. Increasing the amount of alkyl bromide
eventually gave exclusively di-brominated product in
entry 8. Regiochemistry of bromination was assigned
Secondly, ethyl 2-bromopropionate was used to replace
2-bromopentane to enhance brominating reactivity,
which led to successful bromination of those nonactiva-
ted substrates. Without changing other reaction condi-
tions, mono-brominated products were generated with
moderate to good yields, as shown in Figure 2.
Based on our experimental data, we propose the sequen-
tial events for the bromination reaction as depicted in
Scheme 2.
1
by H NMR.11
These results indicate that by using different alkyl bro-
mide, we can generate bromination reagents with differ-
ent bromination reactivity in situ. Thus by the variation
of steric, electronic properties of alkyl bromides, in con-
junction with the stoichiometry of the alkyl bromide
used, we should be able to fine-tune the reactivity of
the bromination reagent according to the reactivity of
a particular aromatic system.
We believe that bromophilic reaction12 between DMSO
and alkylbromide generates the active species for
bromination in situ. DMSO is de-protonated by NaH,
followed by reaction with alkyl bromide, to generate
two intermediates: methyl alkyl sulfide and NaOBr.
NaOBr can either react with sulfide intermediate and
alkyl bromide to produce methyl sulfonium, or react
with alkyl bromide to generate alkoxyhypobromite.
These two intermediates were reported5,13,14 to be active
brominating reagents. It was conceivable that the
To further validate this tunable reactivity concept, we
have extended this brominating system to other aro-
Table 2. Optimization toward bromination only condition (percentage of components as determined by LC–MS using ELSD)
Entry
RBr
Equiv
2
3
4
5
1
2
3
4
5
6
7
8
Bromoethane
2-Bromopropane
2-Bromobutane
2-Bromopentane
Methyl bromoacetate
Ethyl 2-bromopropionate
Ethyl 2-bromoisobutyrate
Ethyl 2-bromopropionate
3
3
3
3
3
3
3
—
—
—
—
—
—
—
—
37
—
—
—
—
—
—
—
49
94
93
98
63
27
76
—
—
—
—
—
33
71
—
95
4 or 5

M. Guo et al. / Tetrahedron Letters 47 (2006) 3889–3892
3891
Conversion (ELSD)
Substrates
Products
H2N
54%
Br
Br
Br
Br
N
N
Br
100%
100%
Br
OMe
Br
80 ºC
18 hrs
+
+
ArH
S
H2N
O
N
N
R
O
N
N
Br-
NaH/DMSO
51% OMe
ROBr
and/or
100%
100%
O
Br
NH2
NH2
86%
Scheme 3. Bromination of unsubstituted aniline analogues.
N
Br
Ph
Br
N
Ph
Ph
Br
system is tunable for different substrates by varying
alkyl bromides.
Ph
100%
91%
N
N
To further support the proposed mechanism, two by-
products of alkyl alcohol and methyl alkyl sulfide from
the reaction were identified, by running the reaction in
N
N
1
OMe
Br
OMe
DMSO-d6 and analyzing H NMR and LC–MS data.
85%
MeO
They were further confirmed by HPLC isolation.15
MeO
OMe
OMe
To expand the limitation of solvents, and eliminating
alkylation reaction, a two-step process was devised.
The first step was to prepare the active brominating
ingredient by heating bromides in DMSO in the pres-
ence of NaH. The second step was to add a solution
of the substrate to the reaction. A list of solvents, includ-
ing DMF, THF, ACN, EtOH, dioxane, or toluene, were
tested to give the positive results shown in Scheme 3.
N
B(OH)2
Br
N
100%
85%
N
Br
N
B(OH)2
Figure 1. Bromination using 2-bromopentane.
In conclusion, a novel tunable aromatic bromination
method was developed using alkyl bromides and DMSO
in the presence of NaH. The ability to modulate the
brominating strength should warrant its applications
in selective bromination on various aromatic systems.
Products
Conversion (ELSD)
65%
Substrates
Br
N
Br
N
Br
NO2
NO2
54%
Acknowledgements
N
N
Br
Authors would like to thank Grace Bi, for the purifica-
tion of selected samples, Jun Zhao, for the LC–MS, and
Norton P. Peet, for helpful discussion.
Br
34%
N
CN
N
CN
References and notes
Figure 2. Bromination using ethyl 2-bromopropionate.
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S
R
NaH
RBr
S
ONa
S
O
+
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+
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+
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Scheme 2. In situ generation of bromination species.
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brominating ability of these could be modulated by the
alkyl group attached to them. Thus, this brominating

3892
M. Guo et al. / Tetrahedron Letters 47 (2006) 3889–3892
9. In a typical experiment, 100 lmol of compound 1 was
BrNO2, 282.04, found, ES+; 283, 285. Compound 3
(R1 = R2 = Et): d (ppm): 7.94 (1H, d, J = 2.8 Hz), 7.63
(1H, d, J = 2.8 Hz), 6.82 (1H, S), 4.58 (1H, S), 1.78 (4H, q,
J = 7.5 Hz), 0.97 (6H, t, J = 7.5 Hz); C12H14Br2NO2,
359.95; found ES+: 361, 363, 365.
dissolved in 500 ll DMSO and placed in a 2-dram vial.
Different amounts (ll) of 0.6 M alkyl halide in DMSO
were added according to the equivalents required, fol-
lowed by a 500 ll suspension of 2% sodium hydride (60%
suspended in mineral oil) in DMSO. The vial was capped
and heated at 80 °C overnight (16 h) with shaking.
Analytical samples were either directly taken from the
reaction mixture or after work-up as follows: 3 ml DCM
was added to the vial, followed by 2 ml of water; the
aqueous phase was discarded after agitation and the DCM
solution was washed twice with 2 ml of water.
12. Zefirov, N. S.; Makhon’kov, D. I. Chem. Rev. 1982, 82,
615–624.
13. Kikuchi, D.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998,
63, 6023–6026.
14. Mach, M. H.; Bunnett, J. F. J. Am. Chem. Soc. 1974, 96,
936–938.
15. EtOCOCH(CH3)CD2SCD3, MS 167.10, found M+
1
10. Fletcher, T. L.; Pan, H. L. J. Am. Chem. Soc. 1956, 78,
4812.
168.15; H NMR (CDCl3): 4.25 (2H, q, J = 6.9 Hz), 3.56
(1H, q, J = 6.9 Hz), 1.42 (3H, d, J = 6.9 Hz), 1.30 (3H,
t, J = 6.9 Hz); EtOCOCH(CH3)OH, 1H NMR (CDCl3):
4.27 (2H, q, J = 7.2 Hz), 3.75 (1H, q, J = 7.2 Hz), 2.5
(1H, b), 1.57 (3H, d, J = 7.2 Hz), 1.32 (3H, t, J =
7.2 Hz).
11. 1H NMR (CDCl3): Compound 2 (R1 = R2 = Et): d (ppm):
7.96 (1H, d, J = 2.1 Hz), 7.35 (1H, dd, J = 2.1, 8.4 Hz),
6.50 (1H, d, J = 8.4 Hz), 6.0 (1H, br s), 4.0 (1H, B), 1.75
(4H, q, J = 7.5 Hz), 0.96 (6H, t, J = 7.5 Hz). C12H15-