A chemoselective, easy bromination of (hydroxymethyl)phenols

Article abstract of DOI:10.1055/s-0028-1083247

A simple and chemoselective method for direct bromination of (hydroxymethyl)phenols via reaction with 2,4,6-trichloro[1,3,5]triazine in N,N-dimethylformamide at room temperature is described. The reaction occurs without affecting the phenolic hydroxy group. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083247

PAPER
3937
A Chemoselective, Easy Bromination of (Hydroxymethyl)phenols
A
C
hemoselective
i
,
E
asy B
a
romination
m
of (Hydroxymethy
ml)Phenols ario Nieddu, Lidia De Luca,* Giampaolo Giacomelli
Dipartimento di Chimica, Università degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
Fax +30(079)212069; E-mail: ldeluca@uniss.it
Received 23 July 2008; revised 4 September 2008
synthesize (bromomethyl)phenols employs methylphe-
nols as starting materials. These reactions proceed as di-
rect radical brominations of the methylphenol but in this
case it is also necessary to perform this conversion with
protection of the phenolic hydroxy function.17 All of the
reported procedures make use of drastic reaction condi-
tions and toxic reagents.
Abstract: A simple and chemoselective method for direct bromina-
tion of (hydroxymethyl)phenols via reaction with 2,4,6-trichlo-
ro[1,3,5]triazine in N,N-dimethylformamide at room temperature is
described. The reaction occurs without affecting the phenolic hy-
droxy group.
Key words: (hydroxymethyl)phenols, cyanuric acid, (bromometh-
yl)phenols, bromination, chemoselectivity
2-(Halomethyl)phenols are not very stable and cannot be
stored for long periods.18 Moreover, weak aqueous bases
transform these compounds into o-quinone methides,19
which rapidly form dimers or trimers.20
(Bromomethyl)phenols are useful intermediates in the
synthesis of some heterocyclic compounds,1,2,3
calix[5]arenes,4 stable metallaquinones as charge-transfer
complexes,5 and titanium trisphenol complexes as catalyt-
ic systems in ring-opening polymerization reactions
(ROP).6 These bromides are also used for the preparation
of pharmacologically active compounds: benzyl-
aptamines, which show significant anticancer and antimi-
crobial activities,7 N-(ureidoalkyl)benzyl-piperidine
derivatives as selective CC Chemokine receptor-3 antag-
onists,8 and sulfonamide analogues with Caspase 3/7 inhi-
bition activities.9
We wish to report here a method which allows the conver-
sion of (hydroxymethyl)phenols into the corresponding
(bromomethyl)phenols. The method is based on the reac-
tion between 2,4,6-trichloro[1,3,5]triazine (TCT) and
DMF, followed by addition of two equivalents of sodium
bromide. To this mixture is then added the (hydroxymeth-
yl)phenol (Scheme 1).21 The reaction is monitored by
TLC until completion. A simple workup consisting of fil-
tration through Celite, aqueous washing, drying over so-
dium sulfate at 0 °C and solvent evaporation, gives the
benzylic bromide (Scheme 1).
Only a few methodologies have been reported in the liter-
ature for the preparation of (bromomethyl)phenols. Some
describe the treatment of (hydroxymethyl)phenols with a
solution of hydrogen bromide in glacial acetic acid at
room temperature.10 Another procedure requires the use
of gaseous hydrogen bromide bubbled into the reaction
mixture.11 An interesting article reports the synthesis of
the amino protecting group ‘Toc’12 by bromination of a-
tocopherol’s benzylic hydroxy group with bromine to
give 5a-bromo-a-tocopherol.13 Rosenau et al. demonstrat-
ed a two-step mechanism for the reaction, as an oxida-
tion–addition mechanism via two-electron processes.
Another approach to (bromomethyl)phenols from (hy-
droxymethyl)phenols consists of treatment with a large
excess of phosphorus tribromide under reflux. The excess
of phosphorus tribromide is removed by vacuum distilla-
tion and the products are recrystallized.14 However, other
authors highlight the need to protect the phenolic hydroxy
group before reacting 3-(hydroxymethyl)phenol with
phosphorus tribromide.15 Chiang et al.16 reported the syn-
thesis of 2-(bromomethyl)phenol employing carbon tetra-
bromide and triphenylphosphine in DMSO. However, the
bromide was not isolated by the authors but immediately
used in the following step. Another method often used to
Cl
N
Cl
R1
R1
N
N
, DMF, NaBr
R3
R2
R3
R2
Cl
Br
OH
CH2Cl2, r.t.
OH
2a–i
OH
R1 = H, Me, Et, i-Bu
1a–i
R
R
2 = H, Br, OMe
3 = H, OMe
Scheme 1
The (hydroxymethyl)phenol starting materials were either
commercially available (Table 1, entries 1 and 5) or pre-
pared as reported in the literature: compounds 1b and 1c
were obtained by reaction of 5-bromo-2-hydroxybenzal-
dehyde with the appropriate Grignard reagent,11b while
compounds 1d and 1f–i were obtained by reduction of the
corresponding aldehyde or ketone.22
This method allows benzylic bromides to be obtained in a
very simple way, employing cheap and easy to handle re-
agents. Furthermore, the use of these reagents permits a
very simple workup, making it possible to prepare sensi-
tive compounds such as 2-(bromomethyl)phenol deriva-
tives.
SYNTHESIS 2008, No. 24, pp 3937–3940
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083247; Art ID: P08208SS
© Georg Thieme Verlag Stuttgart · New York
Because of their sensitivity, 2-(bromomethyl)phenols are
often very difficult to prepare, and purification by chro-

3938
G. Nieddu et al.
PAPER
matography or distillation often causes their decomposi- reaction at the phenolic hydroxy was noted under the re-
tion.
action conditions adopted. After 24 hours, the reactions
were complete in all cases investigated and in the case of
entry 9, the reaction was complete after only three hours.
It is noticeable that by this methodology it is possible to
prepare and isolate 2-(1-bromoalkyl)phenolic compounds
(Table 1, entries 1–3), which are otherwise difficult to We investigated the influence of the phenolic hydroxy
synthesize. We also tested the methodology on the meta group on the behavior of the reaction by examining the
and para regioisomers (Table 1, entries 4–9). In every bromination of some non-phenolic analogues (Table 2).
case the reaction is completely chemoselective because no Compared with reaction times for the bromination of non-
phenolic compounds, the (hydroxyalkyl)phenols are
slower (usually 24 h).
Table 1 Bromination of (Hydroxyalkyl)phenols
Table 2 Effect of a Phenolic Hydroxy Group on Bromination
Entry Alcohol
Product
Yield (%)a
70
Entry Alcohol
R
Time
Yield (%) Chloride
OH
OH
Br
HO
1
1
2
3
H
o-OH
p-OH
15 min
24 h
24 h
98
70
59
no
no
no
OH
1a
2a
OH
Br
R
Br
Br
2
76
73
HO
4
5
6
H
o-OH
p-OH
30 min
24 h
3 h
70
80
87
yes
no
no
OH
OH
OH
Br
1b
2b
R
Br
Br
3
HO
OH
OH
7
8
H
OH
25 min
20 h
78
70
yes
no
1c
Br
2c
Br
Br
OH
OH
Br
Br
4
70
59
R
HO
1d
HO
2d
We also investigated the possible formation of chloride
derivatives as by-products of bromination. We observed
that while bromination of non-phenolic benzylic alcohols
may lead to bromine/chloride mixtures (Table 2, entries 1,
4 and 7), the presence of a phenolic hydroxy group makes
the reaction selective towards bromination (Table 1, all
entries, and Table 2, entries 2, 3, 5, 6 and 8). Phenol-based
substrates, which slow down the reaction rate and there-
fore prevent the chlorination reaction, do not lead to chlo-
rinated products.
5
HO
HO
1e
2e
OH
Br
6
80
61
HO
1f
HO
2f
MeO
MeO
OH
OH
Br
7
In conclusion, our method for the synthesis of (bromo-
methyl)phenols is characterized by mild reaction condi-
tions, easy workup, and commercially available reagents.
The rapid and mild workup conditions allow the isolation
of especially labile 2-(1-bromoalkyl)phenols.
HO
HO
1g
MeO
2g
MeO
Br
HO
HO
8
67
MeO
MeO
All reagents and solvents were obtained from Sigma–Aldrich
Chem. Co. (both Aldrich and Fluka brands), Avocado or Acros Or-
ganics. All solvents were dried by usual methods and distilled under
argon. Petroleum ether (PE) used was the fraction boiling in the
range 40–60 °C. Thin-layer chromatography (TLC) analysis was
performed with Merck Kieselgel 60 F254 plates and visualized us-
ing UV light at 254 nm and KMnO4 staining. 1H NMR (300 MHz)
and proton-decoupled 13C NMR (75.4 MHz) Fourier transform
spectra were obtained with a Varian VXR-300 spectrometer using
CDCl3 solutions and TMS as an internal standard. Chemical shifts
are reported in parts per million (ppm, d) relative to TMS (d = 0.00
ppm) or relative to residual solvent signals (CDCl3, d = 7.27 ppm).
1h
2h
OH
Br
9
87b
OH
OH
2i
1i
a Reaction time of 24 h.
b Reaction time of 3 h.
Synthesis 2008, No. 24, 3937–3940 © Thieme Stuttgart · New York

PAPER
A Chemoselective, Easy Bromination of (Hydroxymethyl)phenols
3939
Coupling constants (J values) are given in Hz. Elemental analyses
4-(1-Bromoethyl)phenol (2f)
were performed on a Perkin–Elmer 420 B analyzer.
Yield: 80%.
1H NMR (CDCl3): d = 8.30 (s, 1 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.10
(d, J = 8.7 Hz, 2 H), 5.09 (q, J = 6.8 Hz, 1 H), 1.80 (d, J = 6.8 Hz,
3 H).
13C NMR (CDCl3): d = 158.6, 127.3, 120.6, 114.9, 57.2, 25.8.
Bromination of 2-(Hydroxymethyl)phenol (2a); Typical Proce-
dure
2,4,6-Trichloro[1,3,5]triazine (TCT; 0.92 g, 5.0 mmol) was added
to DMF (1 mL) and stirred at 25 °C. The mixture was monitored by
TLC until complete disappearance of TCT was observed, then
CH2Cl2 (12.5 mL) was added, followed by NaBr (0.98 g, 9.5 mmol).
The mixture was stirred for 10 h, at which point 2-(hydroxymeth-
yl)phenol (4.7 mmol, 0.58 g) was added. The mixture was stirred at
r.t. until the reaction reached completion (monitored by TLC). The
mixture was filtered through Celite and the organic layer was
washed with H2O (10 mL), HCl (1 N, 2 × 5 mL), and brine (2 × 5
mL). The organic layer was dried over Na2SO3 at 0 °C and the sol-
vent was evaporated to yield 2-(bromomethyl)phenol.
Anal. Calcd for C8H9BrO: C, 47.79; H, 4.51; Br, 39.74. Found: C,
47.76; H, 4.52; Br, 39.73.
4-(1-Bromoethyl)-2-methoxyphenol (2g)
Yield: 61%.
1H NMR (CDCl3): d = 8.22 (s, 1 H), 7.05 (s, 1 H), 6.99 (m, 2 H),
5.05 (q, J = 6.8 Hz, 1 H), 3.83 (s, 3 H), 1.81 (d, J = 6.8 Hz, 3 H).23
13C NMR (CDCl3): d = 158.8, 150.3, 142.1, 122.3, 118.6, 110.8,
58.1, 55.8, 26.4.
Yield: 0.57 g (70%).
Anal. Calcd for C9H11BrO2: C, 46.78; H, 4.80; Br, 34.58. Found: C,
46.75; H, 4.78; Br, 34.55.
1H NMR (CDCl3): d = 6.95 (m, 4 H), 4.53 (s, 2 H).
13C NMR (CDCl3): d = 155.2, 129.9, 129.8, 129.3, 123.3, 118.7,
29.7.
4-(1-Bromoethyl)-2,6-dimethoxyphenol (2h)
Yield: 67%.
Anal. Calcd for C7H7BrO: C, 44.95; H, 3.77; Br, 42.72. Found: C,
44.92; H, 3.76; Br, 42.70.
1H NMR (CDCl3): d = 8.23 (s, 1 H), 6.70 (s, 2 H), 5.04 (q, J = 6.8
Hz, 1 H), 3.84 (s, 6 H), 1.83 (d, J = 6.8 Hz, 3 H).
13C NMR (CDCl3): d = 158.4, 151.5, 141.4, 102.8, 58.4, 55.8, 26.2.
4-Bromo-2-(1-bromopropyl)phenol (2b)
Yield: 76%.
Anal. Calcd for C10H13BrO3: C, 46.00; H, 5.02; Br, 30.60. Found:
C, 46.01; H, 4.99; Br, 30.58.
1H NMR (CDCl3): d = 8.08 (s, 1 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.19
(dd, J = 2.5, 8.6 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 5.21 (m, 1 H),
2.06 (m, 2 H), 1.01 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3): d = 152.6, 131.6, 130.5, 130.1, 117.7, 112.0,
58.9, 31.6, 11.5.
3-(1-Bromoethyl)phenol (2i)
Yield: 87%.
1H NMR (CDCl3): d = 7.95 (s, 1 H), 7.15 (m, 1 H), 6.95 (s, 1 H),
6.88 (d, J = 6.7 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 4.99 (q, J = 6.7
Hz, 1 H), 1.77 (d, J = 6.8 Hz, 3 H).
Anal. Calcd for C9H10Br2O: C, 36.77; H, 3.43; Br, 54.36. Found: C,
36.78; H, 3.41; Br, 54.32.
13C NMR (CDCl3): d = 156.6, 143.9, 129.4, 117.6, 115.2, 113.4,
58.5, 26.1.
4-Bromo-2-(1-bromo-3-methylbutyl)phenol (2c)
Yield: 73%.
Anal. Calcd for C8H9BrO: C, 47.79; H, 4.51; Br, 39.74. Found: C,
47.78; H, 4.53; Br, 39.75.
1H NMR (CDCl3): d = 7.48 (d, J = 2.5 Hz, 1 H), 7.24 (dd, J = 2.5,
6.1 Hz, 1 H), 6.75 (d, J = 8.6 Hz, 1 H), 5.33 (m, 1 H), 2.04 (m, 1 H),
1.81 (m, 2 H), 0.95 (d, J = 6.5 Hz, 6 H).
4-Bromo-2-(1-hydroxypropyl)phenol (1b)
Anal. Calcd for C11H14Br2O: C, 41.03; H, 4.38; Br, 49.62. Found:
C, 41.05; H, 4.37; Br, 49.34.
To a solution of ethylmagnesium bromide [generated from Mg
(0.24 g, 10.00 mmol) and ethyl bromide (1.18 g, 11.00 mmol)] in
anhydrous Et2O (20 mL) at 0 °C, was slowly added (1 h) a solution
of 5-bromo-2-hydroxybenzaldehyde (0.6 g, 3.00 mmol) in Et2O (5
mL). After warming to r.t., the reaction was neutralized with aq HCl
(5%). The organic layer was washed with H2O (3 × 5 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (EtOAc–PE, 2:8) to give 1b.
2-Bromo-4-(bromomethyl)phenol (2d)
Yield: 70%.
1H NMR (CDCl3): d = 7.34 (d, J = 1.8 Hz, 1 H), 6.97 (m, 1 H), 6.85
(d, J = 8.1 Hz, 1 H), 4.34 (s, 2 H).
13C NMR (CDCl3): d = 152.9, 132.1, 130.7, 129.8, 117.4, 112.8,
44.2.
Yield: 0.56 g (81%).
1H NMR (CDCl3): d = 8.06 (s, 1 H), 7.25 (dd, J = 8.6, 2.5 Hz, 1 H),
7.05 (d, J = 2.4 Hz, 1 H), 6.73 (d, J = 8.6 Hz, 1 H), 4.71 (m, 1 H),
2.78 (m, 1 H), 1.85 (m, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).
Anal. Calcd for C7H6Br2O: C, 31.62; H, 2.27; Br, 60.09. Found: C,
31.61; H, 2.24; Br, 60.5.
13C NMR (CDCl3): d = 154.7, 131.5, 129.8, 129.0, 118.9, 111.5,
71.6, 30.1, 9.9.
4-(Bromomethyl)phenol (2e)
Yield: 59%.
1H NMR (CDCl3): d = 8.25 (s, 1 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.09
(d, J = 8.4 Hz, 2 H), 4.54 (s, 2 H).
Anal. Calcd for C9H11BrO2: C, 46.78; H, 4.80; Br, 34.58. Found: C,
46.77; H, 4.80; Br, 34.56.
13C NMR (CDCl3): d = 158.9, 135.4, 129.7, 121.2, 45.1.
Anal. Calcd for C7H7BrO: C, 44.95; H, 3.77; Br, 42.72. Found: C,
44.94; H, 3.75; Br, 42.71.
Acknowledgment
The work was financially supported by the Fondazione Banco di
Sardegna and the University of Sassari (Fondi ex-60%).
Synthesis 2008, No. 24, 3937–3940 © Thieme Stuttgart · New York

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Synthesis 2008, No. 24, 3937–3940 © Thieme Stuttgart · New York