Substitution vs. addition. Regioselective electro-bromination of benzofuran

Article abstract of DOI:10.3987/COM-00-S(I)78

Regioselective electro-bromination of benzofuran (2) was achieved successfully by an adequate choice of solvents and bromide salts to afford 5-bromobenzofuran (1), 5,7-dibromobenzofuran (3), and 2,3-dibromo-2,3-dihydrobenzofuran (4), respectively. Upon electrolysis of benzofuran (2) in AcOH/H₂O (100/1) containing NH₄Br, substitution at the C(5)-position of benzofuran (2) proceeded smoothly to afford 5-bromobenzofuran (1). After passage of totally 4 F/mol of electricity in a similar medium, 5,7-dibromobenzofuran (3) was obtained as a sole product. On the other hand, electrolysis of benzofuran (2) in CH₂Cl₂/H₂O (1/1) and/or AcOH/H₂O (10/1) in the presence of either NaBr or NH₄Br afforded 2,3-dibromo-2,3-dihydrobenzofuran (4), exclusively.

Full text of DOI:10.3987/COM-00-S(I)78

HETEROCYCLES, Vol. 54, No. 2, pp. 825-831, Received, 15th June, 2000
SUBSTITUTION vs ADDITION. REGIOSELECTIVE ELECTRO-
BROMINATION OF BENZOFURAN
Hideo Tanaka,* Yusuke Kawakami, Manabu Kuroboshi, and Sigeru Torii†
Department of Applied Chemistry, Faculty of Engineering,
Okayama University, Tsushima-Naka, Okayama, 700-8530, Japan
e-mail : tanaka95@cc.okayama-u.ac.jp
Abstract - Regioselective electro-bromination of benzofuran (2 ) was achieved
successfully by an adequate choice of solvents and bromide salts to afford 5-
bromobenzofuran (1), 5,7-dibromobenzofuran (3), and 2,3-dibromo-2, 3-
dihydrobenzofuran (4), respectively.
Upon electrolysis of benzofuran (2) in
AcOH/H2 O (100/1) containing NH4 Br, substitution at the C(5)-position of
benzofuran (2 ) proceeded smoothly to afford 5-bromobenzofuran (1 ). After
pas sage o f to tally 4 F /mol o f electricity in a similar med iu m, 5 , 7 -
dibromobenzofuran (3 ) was obtained as a sole product. On the other hand,
electrolysis of benzofuran (2 ) in CH2Cl2/H2O (1/1) and/or AcOH/H2 O (10/1) in the
presence of either NaBr or NH4Br afforded 2,3-dibromo-2,3-dihydrobenzofuran (4),
exclusively.
5-Bromobenzofuran (1), a potent intermediate for synthesis of benzofuran family of bioactive natural
products, has been prepared by multi-step transformation of salicylaldehyde. 1 The most
straightforward route to 5-bromobenzofuran (1) must be bromination of benzofuran (2), but has not yet
been realized so far, presumably due to lack of suitable reagents for regioselective bromination of
benzofuran (2).
for the preparation of bromo-substituted aromatic compounds, e.g., N-acetyl-4-bromoaniline2 and N -
acetyl-5-bromoindoline.3
We investigated electro-bromination of benzofuran (2) as an alternative
Electrochemical bromination has been well recognized to be a promising procedure
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Dedicated to Professor Sho Ito on the occasion of his 77th birthday.

access to 5-bromobenzofuran (1). Herein, we describe regioselective electro-bromination of benzofuran
(2) leading to either 5-bromobenzofuran (1), 5,7-dibromobenzofuran (3), or 2,3-dibromo-2,3-
dihydrobenzofuran (4), respectively, depending on the choice of electrolysis media (Scheme 1).
Br
- e
- e
Br
Br
O
O
NH Br-
O
NaBr-
4
AcOH/H O
CH Cl /H O
2
2
2
2
4
2
1
(100/1)
(1/1)
NH Br-
- e
or
4
AcOH/H O
2
(10/1)
Br
O
Addition vs. Substitution
Br
3
Scheme 1
The electro-bromination of benzofuran (2) was carried out under a constant current density (10 mA/cm2)
in an undivided cell fitted with two platinum foil electrodes (1.5 x 1 cm ). The representative results are
2
shown in Table 1. Electrolysis of benzofuran (2) (1 mmol) in a CH2Cl2/H2O (1/1) two phase solution
(10 mL) in the presence of NaBr (2.1~4.2 equiv.) afforded 2,3-dibromo-2,3-dihydrobenzofuran (4)
(77~84%) after passage of 2.2~4.4 F/mol of electricity (Entries 1 and 2). A similar bromine addition
reaction was performed by use of NH4Br in place of NaBr (Entry 3). In these experiments, any
detectable amounts of the substitution products (1) and (3) were not obtained.
Electro-bromination of benzofuran (2) in AcOH/H2 O (10/1) proceeded in a similar fashion to afford the
addition product (4) though the yields of 4 were slightly less than those above (Entries 4 and 5).
Dramatic change of the products was observed when the amount of water in the electrolysis media was
reduced to 1% (Entries 6~8). Thus, upon electrolysis of benzofuran (2) in AcOH/H2 O (100/1) in the
presence of NH4Br (2.0 equiv. ), regioselective bromination at the C(5)-position of benzofuran (2) took
place to afford 5-bromobenzofuran (1) (48%) together with 5,7-dibromobenzofuran (3) (6%) after
passage of 2.2 F/mol ofelectricity (Entry 6). Continuing electrolysis of benzofuran (2 ) under same
conditions (totally 4.0 F/mol) resulted in the formation of considerable amounts of tarry materials
without detectable amounts of 1 and 3 (Entry 7). The 5,7-dibromobenzofuran (3) was obtained as a
sole product (47%) by the electrolysis (4.0 F/mol) with 4.1 equiv. of NH4Br (Entry 8).

100
50
0
Benzofuran (2)
Monobromide (1)
Dibromide (3)
0
2
4
6
8
Electricity, F/mol
Figure 1
The remarkable change of the products depending on the electrolysis media would be ascribable to
generation of different bromine species in each of the electrolysis systems. In this connection, it is
interesting to note that bromination of benzofuran (2 ) with Br2 (3. 4 equiv. ) in AcOH at room
temperature afforded a mixture of 2,3-dibromo-2,3-dihydrobenzofuran (4) (42%) and 2,3,5-tribromo-2,3-
dihydro-benzofuran (5 ) (28%) after 1 h, and the latter 5 was obtained as an only isolable product (56%)
after 3 h. This fact suggests that Br2 undergoes addition to the C(2)–C(3) double bond of benzofuran
(2), more efficiently than substitution at the C(5)-position.
Br
Br
Br
Br /AcOH
2
Br /AcOH
2
Br
Br
O
slow
O
fast
O
2
4
5
Scheme 2
The difference between the electrolysis media promoting regioselective addition and substitution is the
concentration of water (e.g., Entries 5 and 6). In AcOH/H2O (100/1), only a small part (1 mg/mL) of
NH4Br was dissolved in the media and most of NH4Br remained as solids. On the other hand, much

more NH4Br (20 mg/mL) was dissolved in AcOH/H2O (10/1). The difference in concentration of the
bromide salts in each of the electrolysis media would significantly change the bromine species generated
by electrooxidation of bromide ion.
In a previous paper,4 we reported that either electro-bromination or hydroxybromination of olefins could
be performed successfully by tuning the bromide concentration in aqueous electrolysis media; indeed, at
high concentration of bromide ion (>100 mg/mL), 1, 2-dibromides were exclusively formed, probably via
addition of electrogenerated Br2, while at low concentration of bromide ion (~2 mg/mL), bromohydrines
were obtained as a sole isolable product, presumably via addition of electrogenerated HOBr.
The
present regioselective bromination of benzofuran (2) would be explained in a silimar way by assuming
electrochemical generation of different bromine species, e.g. , Br2 , HOBr, and AcOBr (Scheme 3) .
Thus, upon the electrolysis in an NH4Br-AcOH/H2 O (10/1) system (higher Br– concentration), Br2
generated via two electron oxidation of bromide ion would attack mainly at the C(2)–C(3) double bond of
benzofuran (2 ) leading to the addition product (4). On the other hand, in an NH4Br-AcOH/H2O (100/1)
system (lower Br– concentration), the electrogenerated Br2 would smoothly be hydrolyzed to afford
HOBr (and/or AcOBr),5 which would, in turn, react with benzofuran (2), affording the substitution
products 1 and 3.
- 2e–
2 Br–
Br2
+
+
HOBr
HBr
HBr
Br2
Br2
+
+
H2O
–
fast at lower Br concentration
slow at higher Br concentration
–
AcOH
AcOBr
Scheme 3
In conclusion, regioselective bromination of benzofuran (2 ) leading to addition product (4 ) and
substitution products (1 ) and (3 ) was performed by a proper choice of electrolysis media, e.g., NaBr-
CH2Cl2 /H2O (1/1), NH4Br-AcOH/H2O(10/1), and NH4Br-AcOH/H2O(100/1). The product selectivity
can be reasonably explained by assuming the formation of different active bromine species, e.g., Br2 ,
HOBr, and AcOBr, depending on the bromide ion concentration of each of the electrolysis media.

7.62 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H); IR (KBr) 3022 1612, 1604, 1453, 1336, 1308, 1011 cm- 1.
5,7-dibromobenzofuran (3)7: 1H NMR (200 MHz, CDCl3-Me4Si) d 6.81 (d, J = 2.0 Hz, 1H), 7.61 (d, J =
2.0 Hz, 2H), 7.69 (br s, 2H); IR (KBr) 3022 1611, 1609, 1432, 1313, 1307, 1068 cm- 1.
Bromination of Benzofuran (2) with Bromine in AcOH. To a solution of benzofuran (2) (124 mg,
1.05 mmol) in AcOH (1 mL) (124 mg, 1.05 mmol) was added dropwise a solution of bromine (0.18 mL,
o
o
3.60 mmol) in AcOH (2 mL) at 0~5 C. After being stirred at 0~5 C for 3 h, the reaction mixture was
poured into aqueous saturated Na2SO3 and extracted with ethyl acetate. The extracts were combined,
washed with aqueous suturated NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced
pressure. The residue was chromatographed on a silica gel column (hexane/AcOEt: 30/1) to afford 2,3,5-
1
tribromo-2,3-dihydrobenzofuran (5) (209 mg, 0.58 mmol, 56 %): H NMR (200 MHz, CDCl3-Me4Si) δ
5.70 (s, 1H), 6.87 (s, 1H), 7.55 (s, 1H), 7.64 (s, 1H); IR (KBr) 3042, 1611, 1599, 1452, 1326, 1322, 1085
cm- 1
†Present address: The Institute of Creative Chemistry Co., 874-5, Musa, Okayama 701-2141, Japan.
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