Electrophilic Aromatic Bromination Using Bromodimethylsulfoniuin Bromide Generated in Situ

Article abstract of DOI:10.1021/jo970135w

It has been shown that bromodimethylsulfonium bromide, generated in situ by treating dimethyl sulfoxide with aqueous hydrobromic acid, is a milder and more selective reagent for electrophilic aromatic bromination than elemental bromine.

Full text of DOI:10.1021/jo970135w

J . Org. Chem. 1997, 62, 4321-4326
4321
Electr op h ilic Ar om a tic Br om in a tion Usin g
Br om od im eth ylsu lfon iu m Br om id e Gen er a ted in Situ †
George Majetich,* Rodgers Hicks, and Steven Reister
Department of Chemistry, The University of Georgia, Athens, Georgia 30602
Received J anuary 24, 1997X
It has been shown that bromodimethylsulfonium bromide, generated in situ by treating dimethyl
sulfoxide with aqueous hydrobromic acid, is a milder and more selective reagent for electrophilic
aromatic bromination than elemental bromine.
Positive halogenating agents,1 such as bromodimeth-
ylsulfonium bromide (1), are useful synthetic reagents
because of their ease of preparation2-7 and the wide
variety of transformations they facilitate. For example,
(eq 1)
(eq 2)
(eq 3)
(eq 4)
in 1979, Olah and co-workers reported that the cleavage
of thioketals3 (eq 1) and the oxidative coupling of thiols8
(eq 2) can be achieved with bromodimethylsulfonium
bromide. The addition of 1 across olefinic bonds to
produce sulfonium bromides has also been observed (eq
3).4 The oxidation of acetophenones to glyoxal hydrates
bromination of three aromatic amines on heating with
ethyl bromide in DMSO; an example is shown in
eq 6.10
can be achieved with 1 generated in situ from aqueous
hydrobromic acid in DMSO (eq 4).9 Floyd and co-workers
observed electrophilic aromatic bromination as a side
reaction in several of these oxidations. Under these
conditions, others have also observed aromatic bromina-
tion using bromodimethylsulfonium bromide generated
in situ. Of particular note is the pioneering work of
Megyeri and Keve,7 in which indole alkaloids were
halogenated using reagent 1 (eq 5). During an investiga-
tion of alkylation reactions, Fletcher and Pan noted the
(eq 5)
(eq 6)
† Taken in part from the Ph.D. Dissertation of Rodgers Hicks, The
University of Georgia, 1996.
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) (a) Electrophilic Halogenation: Reaction Pathways Involving
Attack by Electrophilic Halogens on Unsaturated Compounds; de la
Mare, P. B. D., Ed.; Cambridge University Press: London, 1976. (b)
Berliner, E. J . Chem. Ed. 1996, 43, 124.
Despite the broad synthetic utility of bromoarenes,
their preparation using bromodimethylsulfonium bro-
mide has not been systematically investigated. We
therefore undertook a study to establish the scope and
limitations of this bromination procedure and to compare
it to existing methods.
(2) Bromodimethylsulfonium bromide may be prepared in situ from
dimethyl sulfide and elemental bromine,3,4 by the treatment of di-
methyl sulfoxide with aqueous hydrobromic acid,5,6 or by the treatment
of dimethyl sulfoxide with trimethylsilyl bromide.7
(3) Olah, G.; Vankar, D.; Arvanaghi, M.; Prekash, G. Synthesis 1979,
720.
(4) Chow, Y.; Baker, B. Synthesis 1982, 648.
(5) The following mechanism accounts for the formation of bromo-
sulfonium bromide from DMSO and HBr; see: Mislow, K.; Simmons,
T.; Melillo, J .; Ternay, A. J . Am. Chem. Soc. 1964, 86, 1452.
Resu lts a n d Discu ssion
Unactivated arenes, such as benzene, toluene, or
2-methylnaphthalene,11 do not react with 1; hence, an
aromatic ring activated by an electron-donating group
was used to optimize the experimental conditions. We
found that the addition of a large excess of commercial
48% aqueous HBr (>40 equiv) to a solution of 2-meth-
oxynaphthalene (2) in DMSO at room temperature gave
1-bromo-2-methoxynaphthalene (3) in nearly quantitative
(6) Landini, D.; Montari, F. J . Chem. Soc., Chem. Commun. 1968,
86.
(7) Megyeri, G.; Keve, T. Synth. Commun. 1989, 19, 3415.
(8) Olah, G.; Arvanaghi, M.; Vankar, Y. Synthesis 1979, 721.
(9) Floyd, M.; Du, M.; Fabio, P.; J acob, L.; J ohnson, B. J . Org. Chem.
1984, 50, 5022.
(10) Fletcher, T.; Pan, H. J . Am. Chem. Soc. 1956, 78, 4812.
(11) Although 2-methylnaphthalene failed to react with 1, even with
heating, it reacted slowly with elemental bromine to give 1-bromo-2-
methylnaphthalene as well as other inseparable byproducts.
S0022-3263(97)00135-7 CCC: $14.00 © 1997 American Chemical Society

4322 J . Org. Chem., Vol. 62, No. 13, 1997
Majetich et al.
Ta ble 1
Ta ble 2
reaction
condns
yield
of 3 (%)
reaction
completion
solvent
DMSO
2 h at rt
32 h at rt
96
84
complete
trace
unreacted 2
only
unreacted 2
acetonitrile
THF
1 h at reflux
trace
THF
THF/AcOH (3:1)
AcOH/DMSO (2:1) <5 min
24 h at reflux
2 h at rt
99
50
96
complete
∼50% complete
complete
yield within 2 h (eq 7). Treating 2 with 2-20 equiv of
HBr also produces bromide 3; however, these reactions
require longer reaction times in order to reach comple-
tion. A large excess of HBr is therefore used to minimize
reaction times.
(eq 7)
The results of the bromination of 2 with aqueous
hydrobromic acid and dimethyl sulfoxide in other cosol-
vents are summarized in Table 1. Bromination is slow
in acetonitrile and very sluggish in THF; only a trace of
bromide 3 was obtained after 1 h in refluxing THF.
However, the use of acetic acid as a cosolvent greatly
enhances the reaction rate. This observation is consis-
tent with the ionic nature of the electrophilic reagent 1,
which is better solvated and stabilized in a polar medium.
We have established two general protocols for aromatic
bromination with bromodimethylsulfonium bromide gen-
erated in situ. The addition of aqueous hydrobromic acid
to a solution of the substrate in DMSO is hereafter
referred to as general procedure A. In general procedure
B, the DMSO is added to a solution of the substrate in
acetic acid and aqueous hydrobromic acid. Six aryl
methyl ethers were brominated by using general proce-
dures A and B and with bromine in carbon tetrachloride
(general procedure C)12 or in acetic acid (general proce-
dure D)13 (Table 2). In each of these examples, the
bromodimethylsulfonium bromide-based procedures gave
the expected monobromides free of side products. In
contrast, the use of bromine with o-cresol (6) produces
the benzylic bromide, via a free-radical process, while
substrates 4 and 8 gave large quantities of dibromides.
In the case of m-dimethoxybenzene (12), the formation
of dibromide 14 was unavoidable using any conditions
other than reagent 1 and short reaction times.
Phenols and anilines also react with bromodimethyl-
sulfonium bromide generated using 48% aqueous hydro-
bromic acid (Table 3). Normally, the bromination of
aniline in aqueous solvents provides large amounts of the
tribromoaniline product independent of the stoichiometry
of the halogen employed. However, polybromination was
not observed when either aniline (20) or N,N-dimethyl-
aniline (22) was treated with bromodimethylsulfonium
bromide. Twenty grams of 2-methoxynaphthalene (2)
and 2-isopropylphenol (15) were brominated in excellent
yield by using general procedures A and B, demonstrat-
ing the utility of this methodology on a preparative scale.
a
Product contained inseparable impurities. The yield shown
is based on analysis of the 1H NMR spectrum.
The presence of HBr in this bromination procedure and
the need for the aromatic system to be electron-rich
dictate several limitations. Acid-sensitive functionality,
such as acetals or ketals, undergo deprotection before
bromination of the arene occurs. Arenes with electron-
withdrawing substituents, such as a carboxylic acid
group, a nitro group, a halogen substituent, an aldehyde,
a ketone devoid of R-protons (such as benzophenone), or
an ester moiety, fail to react with 1 even under forcing
conditions, while acetophenones produce R-bromo ketones
rather than aromatic bromides.
Furans, even those with electron-withdrawing substit-
uents, typically exhibit high reactivity toward halogena-
tion. Nevertheless, bromination was not observed when
2-furoic acid, R-acetylfuran, or furfuraldehyde were
treated with bromodimethylsulfonium bromide. Pyridine
reacts with mineral acids to form a salt that deactivates
the arene toward electrophilic attack so the halogenation
of pyridine generally requires forcing conditions. Thus,
we were not surprised that pyridine does not react with
the bromodimethylsulfonium bromide even under forcing
conditions (i.e., prolonged reflux). Efforts to brominate
thioanisole with 1 also failed despite a wide variety of
experimental conditions.
(12) Adams, R.; Marvel, C. S. Organic Syntheses; Wiley: New York,
1941; Collect. Vol. I, p 128.
(13) Reference 1a, p 126.
The failure of m-dimethoxybenzene (12) to undergo

Electrophilic Aromatic Bromination
J . Org. Chem., Vol. 62, No. 13, 1997 4323
Ta ble 3
Equation 9 presents three additional examples in
which the reaction temperature governs whether mono-
or dibromination occurs. Treatment of phenol 15 with
(eq 9)
warm HBr, DMSO, and AcOH produces dibromide 17 in
good yield (cf. 15 f 16), whereas bromine in conditions
C and D gave a mixture of bromides 16 and 17. Likewise,
bromination of p-cresol or aniline using the standard
conditions at room temperature gives exclusively the
monobrominated product, whereas the same reactions at
elevated temperatures result in nearly quantitative yields
of dibromide 24 or 25, respectively.
Although aryl chlorides are less synthetically useful
than the corresponding bromides, we were curious to see
whether aryl chlorides could be prepared by generating
chlorodimethylsulfonium chloride (33) in situ.14,15 2-Meth-
oxynaphthalene was treated using general procedure B,
except that aqueous hydrochloric acid was substituted
for hydrobromic acid (eq 10). Unfortunately, chlorination
was not observed at room temperature, and heating the
reaction to reflux gave a poor yield of 1-chloro-2-meth-
oxynaphthalene (34).
a
Inseparable byproducts were observed. The yield shown is
based on analysis of the 1H NMR data.
selective monobromination using reagent 1 prompted us
to study the reaction with veratrole (30) (eq 8). The
(eq 10)
These results indicate that bromodimethylsulfonium
bromide is a milder reagent for electrophilic aromatic
bromination than solutions of bromine. Its greater
selectivity makes it the reagent of choice for the selective
bromination of electron-rich arenes. Moreover, the in situ
generation of bromodimethylsulfonium bromide using
HBr and DMSO eliminates the need to handle the highly
toxic and corrosive bromine as well as the use of carbon
tetrachloride as the reaction medium.16
(eq 8)
activated “4” and “5” positions of veratrole have an ortho-
relationship; thus, the introduction of an electron-
withdrawing halogen at either of these positions will
reduce the activity of the second methoxy group. Given
the mildness of our bromination procedure, it was not
surprising that only monobromination occurs at room
temperature, while a second bromine is introduced upon
heating. Treatment of veratrole with bromine under
conditions C and D afforded inseparable mixtures of
bromides 31 and 32 in the ratio of 2:3 and 3:7, respec-
tively.
Exp er im en ta l Section
Gen er a l P r oced u r es. Standard ethereal workup consisted
of the following procedure: The reaction was cautiously
quenched with saturated aqueous sodium bicarbonate. Vola-
(14) For the reactions of 31 with epoxides and enamines, see: Olah,
G. A.; Vankar, Y. D.; Arvanaghi, M. Tetrahedron Lett. 1979, 38, 3653.
(15) Attempts to extend this methodology for the preparation of aryl
iodides failed as the iododimethyl sulfonium iodide, generated in situ,
rapidly decomposes to produce molecular iodine.

4324 J . Org. Chem., Vol. 62, No. 13, 1997
Majetich et al.
tile organic solvents were removed under reduced pressure on
a rotary evaporator, and the residue was taken up in ether,
washed with brine, and dried over anhydrous magnesium
sulfate. Filtration, followed by concentration on a rotary
evaporator and at 1 Torr to constant weight, provided a crude
residue that was purified by flash chromatography using NM
silica gel 60 (230-400 mesh ASTM) and distilled reagent-grade
solvents. Proton spectra were obtained in CDCl3, except as
noted, and were calibrated using trace CHCl3 present (δ 7.26)
as an internal reference.
6], which was homogeneous on the basis of TLC analysis (H:
E, 1:1, Rf 2 ) 0.85, Rf 3 ) 0.67).
Br om in a tion of 2 in THF . To a stirred solution of 500
mg of 2 (3.2 mmol) in THF (15 mL) was added 5 mL of aqueous
HBr (57 mmol of a 48% solution), followed by the dropwise
addition of 5 mL of DMSO (70.00 mmol). The resulting
mixture was refluxed for 24 h. An aliquot was withdrawn for
1H NMR analysis and was found to contain unreacted 2 and
a trace of bromide 3. Heating was continued for 1 day.
Standard ethereal workup and chromatography (H:E, 20:1
gradient elution to 5:1) gave 759 mg (99%) of 3.
Br om in a tion of 2 in THF /AcOH. To a stirred solution of
500 mg of 2 (3.20 mmol) in THF (15 mL) was added 5 mL of
aqueous HBr (57.00 mmol of a 48% solution) and AcOH (5 mL),
followed by the dropwise addition of 5 mL of DMSO (70.00
mmol). The resulting mixture was stirred at rt for 2 h.
Standard ethereal workup gave a mixture of 3 (<50% by 1H
NMR analysis) and unreacted substrate 2.
Br om in a tion of 2 Usin g Con d ition s A. A reaction
mixture containing 500 mg of 2 (3.20 mmol) was stirred at rt
for 2 h using general procedure A. Standard ethereal workup,
followed by chromatography (elution with H:E, 20:1 gradient
elution to 5:1), provided 720 mg (96%) of bromide 3.
La r ge-Sca le Br om in a tion of 2 Usin g Con d ition s A. To
a stirred solution of 20.00 g (0.15 mol) of 2 in AcOH (400 mL)
and DMSO (100 mL) was added 600 mL of a 48% aqueous
solution of HBr (5.30 mol) over a 5-min period. Analysis by
TLC indicated the reaction was complete after stirring for 5
min at rt. Standard ethereal workup, followed by recrystal-
lization from ethanol, furnished 27.9 g (93%) of bromide 3.
La r ge-Sca le Br om in a tion of 2 Usin g Con d ition s B. To
a stirred solution of 20.00 g (0.15 mol) of 2 in AcOH (200 mL)
was added 100 mL of aqueous HBr (88 mmol of a 48%
solution), followed by the dropwise addition of 100 mL of
DMSO (1.40 mol). Analysis by TLC indicated the reaction was
complete after 5 min at rt. Standard ethereal workup, followed
by chromatography (elution with H:E, 5:1), furnished 28.05 g
(96%) of bromide 3.
Br om in a tion of 2 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 2 (3.20 mmol) was stirred at rt
for 5 min using general procedure C. Standard ethereal
workup, followed by chromatography (elution with H:E, 5:1),
provided 675 mg (90%) of bromide 3.
Br om in a tion of 2 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 2 (3.20 mmol) was stirred at rt
for 5 min using general procedure D. Standard ethereal
workup and chromatography (elution with H:E, 20:1 gradient
elution to 5:1) provided 668 mg (89%) of bromide 3.
Br om in a tion of 1-Meth oxyn a p h th a len e (4) Usin g Con -
d ition s A. A reaction mixture containing 500 mg of 1-meth-
oxynaphthalene (4) (3.20 mmol) was stirred at rt for 72 h using
general procedure A. Standard ethereal workup, followed by
chromatography (elution with H:E, 1:1), provided 578 mg (77%)
of 4-bromo-1-methoxynaphthalene (5) [5467-58-3].
Br om in a tion of 4 Usin g Con d ition s B. A reaction
mixture containing 500 mg of 4 (3.20 mmol) was stirred at rt
for 24 h using general procedure B. Standard ethereal workup
and chromatography (elution with H:E, 1:1) provided 728 mg
(97%) of bromide 5.
Br om in a tion of 4 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 4 (3.20 mmol) was stirred at rt
for 72 h using general procedure C. Standard ethereal workup
and chromatography (elution with H:E, 1:1) provided 675 mg
(90%) of bromide 5.
Chemical Abstracts Service (CAS) registry numbers have
been provided by the authors for known reaction products.
Gen er a l P r oced u r e A: Br om in a tion w ith HBr /DMSO.
To a stirred solution of 500 mg of the substrate in DMSO (15
mL) was added 5 mL of 48% aqueous HBr dropwise. The
reaction progress was monitored by TLC analysis. Heat was
applied only if the reaction required stirring at rt for more
than 3 days to reach completion. The product was isolated
using ethereal workup.
Gen er a l P r oced u r e B: Br om in a tion w ith HBr /DMSO
in Acetic Acid . To a stirred solution of 500 mg of the
substrate in AcOH (10 mL) was added 15 mL of 48% aqueous
HBr. DMSO (5 mL) was added dropwise, and the reaction
progress was monitored by TLC analysis. Heat was applied
only if the reaction was sluggish. The product was isolated
using ethereal workup.
Gen er a l P r oced u r e C: Br om in a tion w ith Br om in e in
Ca r bon Tetr a ch lor id e.12 To a stirred solution of 500 mg of
the substrate in CCl4 (6 mL) was added dropwise a 1.0 M
solution of bromine in CCl4 (2.0 equiv relative to the substrate)
over a 2-min period. The reaction progress was monitored by
TLC analysis. The product was isolated using ethereal
workup.
Gen er a l P r oced u r e D: Br om in a tion w ith Br om in e in
Acetic Acid .13 To a stirred solution of 500 mg of the substrate
in AcOH (6 mL) was added dropwise a 1.0 M solution of
bromine in CCl4 (2.0 equiv relative to the substrate) over a
2-min period. The reaction progress was monitored by TLC
analysis. The product was isolated using standard ethereal
workup.
Br om in a tion of 2-Meth oxyn a p h th a len e (2) Usin g Va r i-
ou s Stoich iom etr ies of HBr . Four identical solutions were
prepared, each containing 500 mg (3.16 mmol) of 2 in a mixture
of 10 mL of acetic acid and 5 mL of DMSO except that 7.5 mL
(66.0 mmol) of 48% aqueous HBr was added to the first
solution, 3.75 mL of 48% aqueous HBr (33.0 mmol) was added
to the second solution, 1.5 mL (13 mmol) of 48% aqueous HBr
was added to the third solution, and 0.75 mL (6.60 mmol) of
48% aqueous HBr was added to the fourth solution. Each
reaction was monitored by TLC analysis. The 2-methoxy-
naphthalene in the first solution using 20.88 equiv of HBr was
completely brominated within a 35-min period in “quantitative
yield” on the basis of NMR analysis. In the second reaction,
using 10.44 equiv of HBr, naphthalene 2 was brominated in
approximately 60% yield after 30 min on the basis of NMR
analysis. In the third experiment, using 1.50 equiv of HBr,
naphthalene 2 was brominated in 33% yield after 35 min on
the basis of NMR analysis. In the fourth reaction, using 2.08
equiv of HBr, naphthalene 2 was brominated in 15% yield after
35 min on the basis of NMR analysis.
Br om in a tion of 2 in Aceton itr ile. To a stirred solution
of 500 mg of 2-methoxynaphthalene (2) (3.20 mmol) in aceto-
nitrile (15 mL) was added 5 mL of aqueous HBr (57 mmol of
a 48% solution), followed by the dropwise addition of 5 mL of
DMSO (70.00 mmol). The resulting mixture was stirred at rt
for 32 h. Standard ethereal workup, followed by chromatog-
raphy (elution with H:E, 5:1), gave 4 mg of unreacted 2 and
640 mg (84%) of 1-bromo-2-methoxynaphthalene (3) [3401-47-
Br om in a tion of 4 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 4 (3.20 mmol) was stirred at rt
for 72 h using general procedure D. Standard ethereal
workup, followed by chromatography (elution with H:E, 1:1),
provided 638 mg (85%) of bromide 5. Impurities arising from
bromination at other positions were detected by 1H NMR
analysis (<5%).
Br om in a tion of o-Meth yla n isole (6) Usin g Con d ition s
A. A reaction mixture containing 500 mg of o-methylanisole
(6) (4.09 mmol) was stirred at rt for 12 h using general
procedure A. Standard ethereal workup and chromatography
(16) Others have recently independently reported the regiospecific
bromination of benzene derivatives with DMSO-HBr. However, this
report lacks detailed experimental procedures so as to allow the
duplication of their results and presents an unlikely mechanism. See:
Srivastava, S. K.; Chauhan, P. M. S.; Bhaduri, A. P. J . Chem. Soc.,
Chem. Commun. 1996, 2679.

Electrophilic Aromatic Bromination
J . Org. Chem., Vol. 62, No. 13, 1997 4325
(elution with H:E, 5:1) provided 675 mg (82%) of 4-bromo-2-
methylanisole (7) [578-58-5].
1) provided 933 mg (89%) of 4,6-dibromo-1,3-dimethoxybenzene
(14) [24988-36-1, H:E, 4:1, Rf 14 ) 0.21].
Br om in a tion of 12 Usin g Con d ition s B for 5 Min . A
reaction mixture containing 500 mg of 12 (3.62 mmol) was
stirred at rt for 5 min using general procedure B. Standard
workup and chromatography (elution with H:E, 10:1) provided
780 mg (73%) of dibromide 14.
Br om in a tion of 6 Usin g Con d ition s B. A reaction
mixture containing 500 mg of 6 (4.09 mmol) was stirred at rt
for 12 h using general procedure B. Standard ethereal workup
and chromatography (elution with H:E, 5:1) provided 708 mg
(86%) of bromide 7.
Br om in a tion of 12 Usin g Con d ition s B for 20 Min . A
reaction mixture containing 500 mg of 12 (3.62 mmol) was
stirred at rt for 20 min using general procedure B. Standard
workup and chromatography (elution with H:E, 10:1) provided
954 mg (87%) of dibromide 14.
Br om in a tion of 6 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 6 (4.09 mmol) was stirred at rt
for 5 min using general procedure C. Standard ethereal
workup, followed by chromatography (elution with H:E, 5:1),
provided 685 mg (75%) of bromide 7.
Br om in a tion of 12 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 12 (3.62 mmol) was stirred at
rt for 5 min using general procedure C. Standard workup and
chromatography (elution with H:E, 10:1) provided 857 mg
(80%) of dibromide 14.
Br om in a tion of 6 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 6 (4.09 mmol) was stirred at rt
for 2 h using general procedure D. Standard ethereal workup,
followed by chromatography (elution with H:E, 5:1), provided
685 mg (75%) of bromide 7.
Br om in a tion of 12 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 12 (3.62 mmol) was stirred at
rt for 5 min using general procedure D. Standard workup,
followed by chromatography (elution with H:E, 10:1), furnished
825 mg (77%) of dibromide 14.
Br om in a tion of 2-Isop r op ylp h en ol (15) Usin g Con d i-
tion s A. To a stirred solution of 20.21 g (0.15 mol) of 15 in
DMSO (150 mL, 2.11 mol) was added dropwise 100 mL of
aqueous HBr (88 mmol of a 48% solution). Analysis by TLC
indicated that the reaction was complete after a 24-h period
at rt. Standard workup, followed by chromatography (elution
with H:E, 4:1), gave 28.70 g (90%) of bromide 16 [26307-50-
6].
La r ge-Sca le Br om in a tion of 15 Usin g Con d ition s B.
To a stirred solution of 20.20 g (0.15 mol) of 15 in AcOH (200
mL) was added 100 mL of aqueous HBr (88 mmol of a 48%
solution), followed by the dropwise addition of 100 mL of
DMSO (1.40 mol). Analysis by TLC indicated that the reaction
was complete after 5 min at rt. Standard ethereal workup,
followed by chromatography (elution with H:E, 1:1), gave 29.05
g (91%) of bromide 16.
Br om in a tion of 15 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 15 (3.67 mmol) was stirred at
rt for 5 min using general procedure C. Standard ethereal
workup and chromatography (elution with H:E, 1:1), gave 173
mg (23%) of bromide 16 [H:E, 2:1, Rf 16 ) 0.81]. Continued
elution afforded 690 mg (64%) of 6-(1-methylethyl)-2,4-dibro-
mophenol (17) [90562-17-7], (H:E, 4:1, Rf 17 ) 0.45).
Br om in a tion of 15 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 15 (3.67 mmol) was stirred for
5 min using general procedure D. Standard ethereal workup,
followed by chromatography (elution with H:E, 1:1), gave 494
mg (63%) of dibromide 16 and 333 mg (31%) of dibromide 17.
Br om in a tion of p-Cr esol (18) Usin g Con d ition s A. A
reaction mixture containing 500 mg of p-cresol (4.63 mmol)
was stirred at rt for 48 h using general procedure A. Standard
workup, followed by chromatography (elution with H:E, 4:1),
gave 763 mg (88%) of 2-bromo-4-methylphenol (19) [6627-55-
0].
Br om in a t ion of 18 Usin g Con d it ion s B. A reaction
mixture containing 500 mg of p-cresol (4.63 mmol) was stirred
at rt for 2 h using general procedure B. Standard workup and
chromatography (elution with H:E, 4:1) provided 750 mg (87%)
of bromide 19.
Br om in a tion of 18 Usin g Con d ition s C. A reaction
mixture containing 500 mg of p-cresol (4.63 mmol) was stirred
at rt for 30 min using general procedure C. Standard workup
and chromatography (elution with H:E, 4:1) provided 756 mg
(87%) of bromide 19 along with a trace amount of 2,6-dibromo-
4-methylphenol (20) [2432-14-6].
Br om in a tion of 18 Usin g Con d ition s D. A reaction
mixture containing 500 mg of p-cresol (4.63 mmol) was stirred
at rt for 30 min using general procedure C. Standard workup
and chromatography (elution with H:E, 4:1) provided 761 mg
(88%) of bromide 19 along with a trace amount of dibromide
20.
Br om in a tion of Va n illin (21) Usin g Con d ition s A. A
reaction mixture containing 500 mg of vanillin (3.29 mmol)
was stirred at rt for 12 h using general procedure A. Standard
Br om in a tion of m -Meth yla n isole (8) Usin g Con d ition s
A. A reaction mixture containing 500 mg of 8 (4.09 mmol)
was stirred at rt for 12 h using general procedure A. Standard
ethereal workup and chromatography (elution with H:E, 10:
1) provided 749 mg (91%) of 4-bromo-3-methylanisole (9) [100-
84-5].
Br om in a tion of 8 Usin g Con d ition s B. A reaction
mixture containing 500 mg of 8 (4.09 mmol) was stirred at rt
for 12 h using general procedure B. Standard ethereal workup
and chromatography (elution with H:E, 10:1) provided 745 mg
(90%) of bromide 9.
Br om in a tion of 8 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 8 (4.09 mmol) was stirred at rt
for 20 min using general procedure C. Standard ethereal
workup and chromatography (elution with H:E, 10:1) provided
561 mg (68%) of bromide 9. Continued elution afforded a
complex mixture of polybrominated products that were not
characterized.
Br om in a tion of 8 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 8 (4.09 mmol) was stirred at rt
for 20 min using general procedure D. Standard ethereal
workup and chromatography (elution with H:E, 10:1) provided
734 mg (89%) of bromide 9. Continued elution afforded a
complex mixture of polybrominated products that were not
characterized.
Br om in a tion of p-Meth yla n isole (10) Usin g Con d ition s
A. A reaction mixture containing 500 mg of p-methylanisole
(10) (4.09 mmol) was stirred at rt for 72 h using general
procedure A. Standard ethereal workup and chromatography
(elution with H:E, 5:1) gave 634 mg (77%) of 2-bromo-4-
methylanisole (11) [104-93-8].
Br om in a tion of 10 Usin g Con d ition s B. A reaction
mixture containing 500 mg of 10 (4.09 mmol) was stirred at
rt for 72 h using general procedure B. Standard ethereal
workup and chromatography (elution with H:E, 5:1) provided
617 mg (75%) of bromide 11.
Br om in a tion of 10 Usin g Con d ition s C. A reaction
mixture containing 500 mg of 10 (4.09 mmol) was stirred at
rt for 20 min using general procedure C. Standard ethereal
workup and chromatography (elution with H:E, 5:1) provided
610 mg (74%) of bromide 11.
Br om in a tion of 10 Usin g Con d ition s D. A reaction
mixture containing 500 mg of 10 (4.09 mmol) was stirred at
rt for 5 min using general procedure D. Standard ethereal
workup and chromatography (elution with H:E, 5:1) provided
792 mg (91%) of bromide 11.
Br om in a tion of m -Dim eth oxyben zen e (12) Usin g Con -
d ition s A for 5 Min . A reaction mixture containing 500 mg
of 12 (3.62 mmol) was stirred at rt for 5 min using general
procedure A. Standard ethereal workup and chromatography
(elution with H:E, 10:1) provided 258 mg of unreacted starting
12 ) 0.60]. Continued elution provided
material [H:E, 4:1, Rf
265 mg (34%) of 1-bromo-2,4-dimethoxybenzene (13) [17715-
69-4, H:E, 4:1, Rf 13 ) 0.50].
Br om in a tion of 12 Usin g Con d ition s A for 20 Min . A
reaction mixture containing 500 mg of 12 (3.62 mmol) was
stirred at rt for 20 min using general procedure A. Standard
ethereal workup and chromatography (elution with H:E, 10:

4326 J . Org. Chem., Vol. 62, No. 13, 1997
Majetich et al.
workup and chromatography (elution with H:E, 5:2) provided
546 mg (72%) of 3-bromo-4-hydroxy-5-methoxybenzaldehyde
(22) [2973-76-4].
Br om in a tion of 21 Usin g Con d ition s B. A reaction
mixture containing 500 mg of vanillin (3.29 mmol) was stirred
at rt for 12 h using general procedure B. Standard workup,
followed by chromatography (elution with H:E, 5:2), provided
433 mg (57%) of 22.
Br om in a tion of 27 Usin g Con d ition s D. A reaction
mixture containing 500 mg (4.13 mmol) of 27 was prepared
using general procedure D and stirred at rt for 5 min. The
reaction mixture was diluted with water and made basic by
the slow addition of solid NaOH. Standard workup and
chromatography (H:E, 1:1) gave 560 mg (68%) of bromide 28
and 335 mg (29%) of 2,4-dibromo-N,N-dimethylbenzenamine
(29) [64230-2-9].
Br om in a tion of Ver a tr ole (30) Usin g Con d ition s A. A
reaction mixture containing 500 mg of veratrole (3.62 mmol)
was stirred at rt for 24 h using general procedure A. Standard
workup and chromatography (elution with H:E, 10:1) provided
688 mg (87%) of 4-bromoveratrole (31) [2859-78-1].
Br om in a tion of 30 Usin g Con d ition s B. A reaction
mixture containing 500 mg of veratrole (3.62 mmol) was stirred
at rt for 24 h using general procedure B. Standard workup
and chromatography (elution with H:E, 10:1) provided 566 mg
(72%) of bromide 31.
Br om in a tion of 21 Usin g Con d ition s C. A reaction
mixture containing 500 mg of vanillin (3.29 mmol) was stirred
at rt for 24 h using general procedure C. Standard ethereal
workup, followed by chromatography (elution with H:E, 5:2),
provided 192 mg of unreacted vanillin and 364 mg (48%) of
bromide 22.
Br om in a tion of 21 Usin g Con d ition s D. A reaction
mixture containing 500 mg of vanillin (3.29 mmol) was stirred
at rt for 20 min using general procedure D. Standard ethereal
workup, followed by chromatography (elution with H:E, 5:2),
provided 759 mg (80%) of 22.
Br om in a tion of 30 Usin g Con d ition s B a t Reflu x.
A
Br om in a tion of An ilin e (23) Usin g Con d ition s A.
A
reaction mixture containing 500 mg of veratrole (3.62 mmol)
was prepared using general procedure B and refluxed for 2 h.
Standard workup and chromatography (elution with H:E, 10:
1) provided 803 mg (75%) of 4,5-dibromo-1,2-dimethoxybenzene
(32) [37875-73-1].
Br om in a tion of 30 Usin g Con d ition s C. A reaction
mixture containing 500 mg of veratrole (3.62 mmol) was
prepared using general procedure C and was stirred at rt for
5 h. Standard workup provided 774 mg of a mixture of
bromides 31 and 32. On the basis of NMR analysis of this
residue, bromide 31 was produced in 52% yield, while dibro-
mide 32 was produced in 35% yield.
Br om in a tion of 30 Usin g Con d ition s D. A reaction
mixture containing 500 mg of veratrole (3.62 mmol) was
prepared using general procedure D and was stirred at rt for
2 h. Standard workup and chromatography (elution with H:E,
10:1) provided 613 mg of a mixture of bromides 31 and 32. On
the basis of NMR analysis of this residue, bromide 31 was
produced in 49% yield, while dibromide 32 was produced in
21% yield.
Br om in a tion of 2-Isop r op ylp h en ol (15) Usin g Con d i-
tion s B a t Reflu x. A reaction mixture containing 500 mg
(3.67 mmol) of 15 was stirred at rt for 5 min using general
procedure B. The mixture was then refluxed for a 2-h period.
Standard ethereal workup, followed by chromatography (elu-
tion with H:E, 4:1), provided 860 mg (80%) of dibromide 17.
reaction mixture containing 500 mg (5.37 mmol) of aniline was
stirred at rt for 6 h using general procedure A. The reaction
mixture was diluted with water and made basic by the slow
addition of solid NaOH. Standard ethereal workup, followed
by chromatography (elution with H:E, 5:1), gave 705 mg (76%)
of 4-bromoaniline (24) [106-40-1], which was homogeneous by
TLC analysis [H:E, 1:2, Rf 23 ) 0.55, Rf 24 ) 0.70].
Br om in a tion of 23 Usin g Con d ition s B. A reaction
mixture containing 500 mg (5.37 mmol) of aniline was stirred
at rt for 2 h using general procedure B. The reaction mixture
was diluted with water and made basic by the slow addition
of solid NaOH. Standard ethereal workup, followed by chro-
matography (elution with H:E, 5:1), gave 685 mg (74%) of
bromide 24. No further bromination resulted when the above
conditions were maintained for a 6-h period.
Br om in a tion of 23 Usin g Con d ition s C. A reaction
mixture containing 500 mg (5.37 mmol) of aniline was stirred
at rt for 5 min using general procedure C. The reaction
mixture was diluted with water and made basic by the slow
addition of solid NaOH. Standard ethereal workup and
chromatography (H:E, 5:1) gave 179 mg (19%) of bromide 24.
Continued elution furnished 449 mg (33%) of 2,4-dibromoben-
zeneamine (25) [615-57-6] and 350 mg (30%) of 2,4,6-tribro-
mobenzenamine (26) [147-82-0].
Br om in a tion of 23 Usin g Con d ition s D. A reaction
mixture containing 500 mg (5.37 mmol) of aniline was stirred
at rt for 5 min using general procedure D. The reaction
mixture was diluted with water and made basic by the slow
addition of solid NaOH. Standard workup and chromatogra-
phy (H:E, 5:1) gave 201 mg (21%) of bromide 24. Continued
elution furnished 549 mg (41%) of dibromide 25 and 361 mg
(31%) of tribromide 26.
Br om in a tion of p-Cr esol (18) Usin g Con d ition s B a t
Reflu x. A reaction mixture containing 500 mg (4.63 mmol)
of 18 was prepared using general procedure B except that the
reaction mixture was refluxed for 2 h. Standard ethereal
workup, followed by chromatography (elution with H:E, 4:1),
provided 965 mg (99%) of dibromide 20.
Br om in a tion of p-Br om oa n ilin e (24) Usin g Con d ition s
B a t Reflu x. A reaction mixture containing 500 mg (2.90
mmol) of p-bromoaniline (24) was prepared using general
procedure B and heated at reflux for 4 h. The reaction mixture
was diluted with water and made basic by the slow addition
of solid NaOH. Standard workup and chromatography (H:E,
5:1) gave 959 mg (82%) of tribromide 26.
P r ep a r a tion of 1-Ch lor o-2-m eth oxyn a p h th a len e (34).
To a stirred suspension of 500 mg (3.20 mmol) of 2 in AcOH
(15 mL) was added 5 mL of aqueous HCl (61.0 mmol of a 37%
solution) followed by the dropwise addition of 5 mL of DMSO
(70.00 mmol). During this addition the substrate dissolved.
The reaction mixture was stirred for 30 min at rt and then
refluxed for 20 min. Standard ethereal workup, followed by
chromatography (elution with H:E, 10:1 gradient elution to
2:1), gave 170 mg (28%) of chloride 34 [13101-92-3]. Continued
elution gave a complex mixture of compounds.
Br om in a tion of N,N-Dim eth yla n ilin e (27) Usin g Con -
d ition s A. A reaction mixture containing 500 mg (4.13 mmol)
of 27 was stirred at rt for 24 h using general procedure A.
The reaction mixture was diluted with water and made basic
by the slow addition of solid NaOH. Standard workup and
chromatography (H:E, 1:1) gave 356 mg of bromide 28 (43%)
[586-77-6], which was homogenous by TLC analysis as well
as unreacted 27.
Br om in a tion of 27 Usin g Con d ition s B. A reaction
mixture containing 500 mg (4.13 mmol) of aniline 27 was
stirred at rt for 24 h using general procedure B. The reaction
mixture was diluted with water and made basic by the slow
addition of solid NaOH. Standard workup, followed by chro-
matography (H:E, 1:1), gave 555 mg of a 1:1 mixture of 28
and unreacted 27. On the basis of NMR analysis, this
corresponds to a 42% yield of bromide 28.
Br om in a tion of 27 Usin g Con d ition s C. A reaction
mixture containing 500 mg (4.13 mmol) of 27 was prepared
using general procedure C and stirred at rt for 5 min. [Note:
Solids formed on addition of the Br2.] The reaction mixture
was diluted with water and made basic by the slow addition
of solid NaOH. Standard workup, followed by chromatography
(H:E, 1:1), gave 498 mg of bromide 28 (60%).
Ack n ow led gm en t. Special thanks are extended to
Travis Blake and Patrick McGill for their experimental
assistance.
J O970135W