Investigations into the bromination of substituted phenols using diethyl bromomalonate and diethyl dibromomalonate

Article abstract of DOI:10.1246/bcsj.74.179

Substituted 4-bromophenols can be synthesised efficiently by heating the corresponding phenol in either neat diethyl bromomalonate or diethyl dibromomalonate. We discuss the regioselectivity of such reactions and comment on the scope and limitation of this procedure.

Full text of DOI:10.1246/bcsj.74.179

Short Articles
Bull. Chem. Soc. Jpn., 74, 179–180 (2001) 179
transfer occurs using the diethyl bromomalonate (1) [to give
phenol (4)] due to the presence of the mildly acidic proton, but
the rate is presumably slower than the dibromomalonate cases
due to competing H-transfer. The progress of the both reactions
can easily be monitored by TLC, by the formation of the by-
products diethyl malonate and diethyl bromomalonate (1).
The remaining substituted phenols (5), (8), (10), (13) and
Investigations into the Bromination
of Substituted Phenols using Diethyl
Bromomalonate and Diethyl
Dibromomalonate
(16) behaved similarly. Bromination of the 1-napthanol (5)
gave a mixture of 4-bromo- and 2,4-dibromophenol (6) and (7)
respectively in good yield (Table 1). Bromination always oc-
curs within the same aromatic ring as the directing OH group.
This mixture can be prevented if an electron-donating group
was positioned in both rings. Whereas, treatment of 1,5-dihy-
droxynapthalene diol (8) under our standard conditions gave
the 4-bromophenol (9) in very poor yield, presumably due to
additional peri-strain within the transition state.
Gregory Socrates Coumbarides, Marco Dingjan,
Jason Eames,* and Neluka Weerasooriya
Department of Chemistry, Queen Mary,
University of London, Mile End Road, London E1 4NS, UK
(Received July 12, 2000)
Bromination can efficiently occur at the C2 position when
more favored C4 position was blocked. Treatment of the sym-
metrical phenol hydroquinone (10) with diethyl bromo-
malonate (1) and diethyl dibromomalonate (2) gave a mixture
of monobromophenol (11) (major) and dibromophenol (12)
Substituted 4-bromophenols can be synthesised effi-
ciently by heating the corresponding phenol in either neat di-
ethyl bromomalonate or diethyl dibromomalonate. We dis-
cuss the regioselectivity of such reactions and comment on
the scope and limitation of this procedure.
(minor) in 85–91% yield. The isomeric phenol, resorcinol (13)
and the 2,2′-biphenyl diol (16) were identical giving the 4-bro-
mophenol (14) and 5-bromo-2,2′-biphenyl diol (17) in excel-
lent yield (Table 1).
Attempts at brominating less nucleophilic phenols, such as
the deactivated ortho-, meta- and para-nitrophenols proved un-
Electrophilic bromination of substituted phenols is well doc-
1
umented. A wide variety of efficient electrophilic brominating
2
3
reagents have been used, such as Br and N-bromosuccinim-
2
4
ide (NBS) which appear to be the most commonly used meth-
od. The presence of additives, such as strong acids are general-
ly required to catalyze the reaction and basic amines to control
Table 1. The Synthesis and Yield(%) of Bromophenols
5
6
the regioselectivity. Consequently, many of these methods re-
quire the reaction to be performed in either acidic or basic con-
ditions. We were interested in developing a novel bromination
6
Entry Starting material
1
Product
Reagent
Yield/%
procedure that could be performed under much milder condi-
tions. We chose to investigate the use of diethyl bromo-
malonate (1) and dibromomalonate (2) as electrophilic bromi-
nating reagents, primarily due to their commercial availability
and structural similarity to the less reactive N-bromosuccinim-
ide (NBS), but more importantly because the near neutral con-
ditions would be preserved due to formation of the relatively
non-acidic by-product diethyl malonate or diethyl bromo-
malonate (1). The use of such reagents are rare, but there is a
report where both react efficiently with very labile ester eno-
1
2
82
82
2
1
2
6; 48, 7; 51
6; 32, 7; 45
3
4
1
8
7
lates. Herein, we report our study into the use of both reagents
1
2
11; 80, 12; 11
11; 68, 12; 17
as electrophilic Br-sources with phenol derivatives and com-
ment on the scope and limitation of this procedure. The opti-
mum conditions for efficient bromination were found to re-
quire direct heating of the substituted phenol in either neat di-
ethyl bromomalonate (1) (1 molar amount) or diethyl dibromo-
malonate (2) (0.5 molar amount) at 100 °C for 2 days; for ex-
ample, treatment of simple phenol (3) under such conditions
gave exclusively the 4-bromophenol (4) in good yield [82% in
both cases using either (1) or (2)]. Both reagents behave simi-
larly, giving the same regioisomer in good yield, but the reac-
tion times were marginally shorter for the more electrophilic
dibromomalonate (2). It is quite remarkable that efficient Br
5
6
1
2
14; 67, 15; 23
14; 91, 15; 0
1
2
17; 99
17; 99

1
80 Bull. Chem. Soc. Jpn., 74, No. 1 (2001)
© 2001 The Chemical Society of Japan
successful — even on prolonged heating — and were re-isolat-
ed in near quantitative yield. The question remained whether
the phenol or the phenolate was the active component in this
reaction. By comparison, reacting the protected phenol in the
form of anisole with both electrophilic bromomalonates (1)
and (2) gave only recovered starting material, presumably indi-
cating that formation of the more nucleophilic phenolate was
responsible for the addition to poor electrophilic brominating
reagents.
tion of diethyl dibromomalonate (1.0 g, 0.71 ml, 4.18 mmol). This
solution was heated at 100 °C for 2 days and allowed to cool to
room temperature. The residue was purified by flash column chro-
matography on silica gel eluting with CH Cl to give 2-bromophe-
2
2
nol (11) (0.64 g, 80%) as a white needles, mp 106–109 °C
(
CH Cl ); R [CH Cl ] 0.1; IR (CHCl ) 3600–3000 (broad OH),
577 and 1560 cm (C=C). H NMR (250 MHz, DMSO-d ) δ
6
2 2 f 2 2 3
–
1
1
1
9
6
.30 (1 H, s, OH), 9.0 (1 H, s, OH), 6.90 (1 H, d, J = 1.5, CH; Ar),
13
.85 (1 H, d, J = 6.0 and 1.5 Hz, CH; Ar). C NMR (67.5 MHz,
DMSO-d ) δ 152.6, 146.9, 119.2, 117.2, 115.7 and 109.4. Found:
6
Discrimination between these reagents can be seen by using
more basic aromatic systems, such as aniline (18). With diethyl
bromomalonate (1), deprotonation occurs to give the ammoni-
um salt (19) in near quantitative yield, whereas partial bromi-
nation does occur with dibromomalonate (2) to give 4-bromo-
aniline (20) (20%) (Scheme 1). The yield was much lower than
the corresponding phenol (82%) due to the formation of the
acidic by-product 1 which subsequently protonates the original
aniline. Attempts at brominating less nucleophilic alkyl-substi-
tuted aromatics, such as toluene, also proved unsuccessful and
gave recovered starting material in near quantitative yield.
In conclusion, we have shown that substituted 4-bromo-
phenols can be synthesised efficiently in good yield by heating
the corresponding phenol in either neat diethyl bromomalonate
m/z, 187.9402. Calcd for C H BrO M, 187.9473. MS m/z 189.9
6
5
79
2
8
1
(100, M ) and 187.9 (100, M ); and dibromophenol (12) (0.13 g,
11%) as white needles, mp 159–162 °C; R [CH Cl ] 0.2; IR
f
2
2
–
1
(CHCl
3
) 3600–3000 (broad OH), 1580 and 1560 cm (C=C);
H NMR (250 MHz, DMSO-d ) δ 9.75 (2 H, s, 2 × OH) and 7.05
2 H, s, 2 × CH; Ar); C NMR (67.5 MHz, DMSO-d ) δ 147.6,
1
6
1
3
(
6
1
2
6 5 2 2
19.7 and 108.6. Found m/z, 265.8579. Calcd for C H Br O M,
65.8578. MS m/z 267.9 (100, M ) and 265.9 (100, M ).
8
1
79
General Procedure with Diethyl Bromomalonate (2): Hy-
droquinone (10) (0.35 g, 3.14 mmol) was added to a stirred solu-
tion of diethyl bromomalonate (0.5 g, 0.3 ml, 1.6 mmol). This so-
lution was heated at 100 °C for 2 days and allowed to cool to room
temperature. The residue was purified by flash column chroma-
tography on silica gel eluting with CH Cl to the 2-bromophenol
2
2
(11) (0.40 g, 68%) and 2,5-dibromophenol (12) (0.14 g, 17%),
(
1) or diethyl dibromomalonate (2). The reaction was shown to
be particularly sensitive to the substitution pattern, and the
presence of both electron withdrawing groups (such as NO
identical to that obtained previously.
2
)
We thank Queen Mary (University of London), the London
University Central Research Fund and The Nuffield Founda-
tion (NUF-NAF 99) for financial assistance.
and protecting the phenolic OH group, which have been shown
to hinder this electrophilic bromination reaction. Both reagents
are similarly high yielding, but the less reactive bromo-
malonate (1) appears to be the better reagent due to the ease of
purification.
References
1
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Experimental
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General Procedure with Diethyl Bromomalonate (1): Hy-
droquinone (10) (0.46 g, 4.18 mmol) was added to a stirred solu-
7