Regioselective monobromination of free and protected phenols

Article abstract of DOI:10.1002/ejoc.200600971

A comparative study of the advantages of using THF compared with DMF in regioselective monobromination reactions of highly activated polyphenols, their ethers, and their tert-butyl carbonate derivatives under mild conditions is described. Bromination with

Full text of DOI:10.1002/ejoc.200600971

FULL PAPER
DOI: 10.1002/ejoc.200600971
Regioselective Monobromination of Free and Protected Phenols
Daniel Pla,[a] Fernando Albericio,*[a,b] and Mercedes Álvarez*[a,c]
Keywords: N-Bromosuccinimide / Aromatic substitution / Phenols / Alkoxybenzenes / Bromobenzene / Regioselectivity
A comparative study of the advantages of using THF com-
pared with DMF in regioselective monobromination reac-
tions of highly activated polyphenols, their ethers, and their
tronically favored positions with respect to O-substituents.
Tight control of the reaction temperature as well as short re-
action times afforded better isolated yields (from 70% to
tert-butyl carbonate derivatives under mild conditions is de- quantitative) of bromides when THF was used as the solvent
scribed. Bromination with the common reagent N-bromosuc-
cinimide in polar solvents provided an easy and fast ap-
proach to aromatic electrophilic substitution at the most elec-
instead of the classically used DMF.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
V2O5/H2O2, supported reagent systems such as NaClO2,
NaBr, and Mn(acac)3 with Montmorillonite K10 or moist-
ened silica gel.[11] The harsh reaction conditions associated
with most bromination methods, namely the use of bromine
and the consequent formation of polyhalogenated byprod-
ucts, has led to the development of reagents such as pyridi-
nium bromide perbromide[12] which can be used preformed
or can be generated in situ by the addition of pyridine to
bromine.[13] N-Bromosuccinimide (NBS) has previously
been used for the bromination of the aforementioned class
of trihydroxy and trialkoxy substrates, whether in CCl4 or
with the heterogeneous system CCl4/SiO2 as Lewis acid to
promote nuclear bromination.[14] Aromatic electrophilic
substitution of activated systems with NBS is generally fa-
vored in polar solvents such as DMF and CH3CN.[15] Ionic
liquids[16] such as 1-butyl-3-methylimidazolium hexafluoro-
phosphate have recently been reported as the solvents of
choice for these kinds of substrates. We report herein a new
and mild procedure for the regioselective monobromination
of benzenetriol, its methyl and isopropyl ethers, and its tert-
butyl carbonate.
Introduction
Chemical functionalization of substituted benzenes pro-
vides compounds capable of modulating the physico-chemi-
cal and/or biological activities of natural products. Safra-
mycins,[1] renieramycins,[2] ningalins,[3] ecteinascidins,[2c,2d,4]
and lamellarins are an important group of marine natural
products[5] possessing as a common structural motif poly-
hydroxy- and polymethoxybenzenes. These privileged struc-
tures are characterized by their cytotoxic activity and po-
tential utility for cancer chemotherapy. Many total synthe-
ses are based on Pd0-catalyzed cross-coupling reactions
leading to C–C bond formation.[6] Sequential regioselective
bromination and Suzuki cross-coupling reactions have been
used in the total synthesis of lamellarin D and in the prepa-
ration of a library of lamellarin analogues.[7]
Bromo- and iodobenzenes have been extensively used in
cross-coupling reactions as reagents or precursors of the or-
ganometallic required for each reaction. Thus, efficient
methodologies for the preparation of OH/OMe-substituted
halobenzenes are required. Bromination of trihydroxybenz-
enes and their ether derivatives has been achieved using di-
verse combinations of reagents and conditions, the most
common of which is bromine in halogenated solvents (e.g., Results and Discussion
CCl4 and CHCl3[8]) or in AcOH.[9] Bromination reactions
The bromination reactions of trioxybenzenes using
have also been carried out with bromine with catalysts such
freshly crystallized NBS in either DMF or THF were evalu-
ated. We chose these two highly polar solvents as it is
known that polar solvents drive the bromination reaction
through the stabilization of bromocyclohexadienone-type
intermediates.[17] DMF[18] as well as MeCN[15] have been
described previously as good solvents for nuclear bromina-
tion reactions of aromatic systems with NBS. However, the
bromination of a polyphenol with NBS in THF has only
been reported once,[19] and has only rarely been used for
the bromination of monosubstituted methoxy- or benzyloxy-
anilines.[20]
as CF3CO2Ag,[10] tetrabutylammonium bromide with
[a] Institute for Research in Biomedicine, Barcelona Science Park-
University of Barcelona,
Josep Samitier 1–5, 08028 Barcelona, Spain
E-mail: malvarez@pcb.ub.es
[b] Department of Organic Chemistry, University of Barcelona,
08028 Barcelona, Spain
[c] Laboratory of Organic Chemistry, Faculty of Pharmacy, Uni-
versity of Barcelona,
08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 1921–1924
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1921

D. Pla, F. Albericio, M. Álvarez
FULL PAPER
To the best of our knowledge, no comparative study on curred only at positions 4 and 6 (ortho with respect to R4,
the role of solvent in polyphenols of benzenes has ever double favored effect), respectively, with no reaction ob-
been carried out. The results of attempts to regioselec- served at the less hindered position 5 (meta with respect to
tively brominate 1a–g in THF and DMF are detailed in R4, only one favored effect). The regioselectivity was evalu-
Table 1. Reaction progress was monitored by HPLC. ated through a NOESY (nuclear Overhauser effect spec-
Good-to-excellent yields of regioselectively monobromin- troscopy) experiment. Formation of 6-bromo-2,3-dimeth-
ated compounds were obtained. DMF and THF per- oxyphenol (2b) instead of the 4-bromo derivative was dem-
formed similarly in the bromination of the alkoxy-pro- onstrated by the positive NOE between C3–OMe (singlet at
tected phenols, but THF gave higher yields with phenols δ = 3.83 ppm) and the proton at position 4 (doublet at δ =
(entries 1–4). Low-temperature reactions in THF probably 6.40 ppm) of the benzene ring (see the Supporting Infor-
allow more selectivity by avoiding polybromination and mation). The para disposition of the aromatic protons of
decomposition processes. Bromination of 1b in DMF at compounds 2d–g was demonstrated by the presence of two
1
room temperature (entry 3) gave a mixture of the starting singlets in their respective H NMR spectra. Bromination
material [retention time (tr) = 3.6 min], 2b (tr = 6.2 min), of 1d–g (entries 5–9) occurred only at position 5 (ortho with
a regioisomer (tr = 6.6 min), and a dibromo derivative (tr respect to R4, double favored effect), with no reaction at
= 9.7 min). However, when this reaction was performed at position 3 (bis ortho). These results clearly indicate that
–60 °C, the freezing point of DMF, 2b was obtained in electronic effects are more important than steric effects in
a yield of 28%. Although these reaction conditions were determining the orientation of electrophilic substitution.
suitable for the monobromination of phenols with OH/ For instance, bromination of 1f occurred at position 5, or-
OMe groups in positions 2 and 3 (entries 1–3), yields de- tho to the isopropyloxy group, which is more hindered than
creased dramatically with 1,2,4-trisubstituted phenols and the methoxy group, but not at position 3, where steric hin-
methoxyphenols in both solvents. Bromination of 1,2,4- drance was too great.
trihydroxybenzene (1c) in THF at –78 °C gave 2c in 17%
The reaction times of these reactions are related to the
yield. The same reaction in DMF led to decomposition of nature of the oxygenated substituents. Phenols (entries 1–4)
the starting material (entry 4). In both cases (THF, DMF, required longer reaction times than methoxy or isopropyl
entry 4) decomposition was observed during the purifica- ethers (entries 5–7). Boc-protected phenol 1g required a
tion process as a dark material adhered to the alumina higher temperature and longer reaction time (entry 9).
pad. In contrast, excellent reaction yields were obtained Attempts to brominate 1g at –78 °C were unsuccessful (en-
for protected 1,2,4-trihydroxybenzenes. Bromination of 1d try 8), however, high yields and regioselectivity were ob-
in THF and in DMF afforded 2d in 96 and 89% yields, tained for this reaction in DMF and THF at 0 °C.
respectively.
The preparation of 2g is an example of a bromination of
The regioselectivity of the process was directed through a diprotected 1,3-dihydroxy-4-methoxybenzene in which the
a combination of electronic and steric effects enhanced by two protecting groups can be selectively removed under
temperature control. Thus, bromination of 1a and 1b oc- controlled acidic conditions.[21]
Table 1. Bromination of phenols and phenoxy ethers.
Entry
Comp.
R1
R2
R3
R4
THF
T /°C
DMF
T /°C
t /min
% yield[a]
t /min
% yield[a]
1
2
3
4
5
6
7
8
9
a
b
b
c
d
e
f
H
H
H
OH
OiPr
OMe
OMe
OMe
OMe
OH
OH
OMe
OMe
H
H
H
H
H
H
OH
OH
OH
OH
OiPr
OMe
OiPr
OiPr
OiPr
60
70
45
60
15
15
10
60
45
–78
–78
25
–78
–78
–78
–78
–78
0
92
70
67
17
96
45
45
45
45
15
15
15
–
0
–60
25
0
0
0
0
–
0
39
28
OMe
OMe
OH
OiPr
OiPr
OiPr
OBoc
OBoc
36[b]
dec.[c]
89
95
95
96
quant.[d]
n.r.[e]
quant.[d]
g
g
–
45
quant.[d]
[a] Yields of isolated products unless specified. [b] Percentage of 2b in the reaction crude, as measured by HPLC, which also contained
38% of a regioisomer and 5% of a dibromo-2,3-dimethoxyphenol. [c] A complex mixture of decomposition products was obtained. [d]
quant. = quantitative yield. [e] n.r. = no reaction, the starting material 1g was recovered.
1922
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Eur. J. Org. Chem. 2007, 1921–1924

Regioselective Monobromination of Phenols
FULL PAPER
98.3 (d), 104.8 (d), 115.3 (s), 141.8 (s), 144.4 (s), 149.4 (s) ppm. MS
In conclusion, an effective procedure for the regioselec-
tive monobromination of activated phenols, their ethers,
and Boc derivatives has been developed. THF was found to
be a better solvent than DMF for free phenol substrates,
however, similar yields were obtained for both solvents in
the reactions of methoxy and protected phenols.
(ESI-TOF): m/z (%) = 203 (100) [MBr79], 205 (97) [MBr81].
1-Bromo-2,4,5-tris(isopropyloxy)benzene (2d): Starting from 1,2,4-
tris(isopropyloxy)benzene (4.01 g, 15.9 mmol), 2d (5.05 g,
15.3 mmol, 96%) was obtained as a yellowish oil using THF as
solvent. IR (film): ν = 2976, 2932, 1489, 1384, 1200, 1109 cm–1. 1H
˜
NMR (400 MHz, CDCl3, 25 °C): δ = 1.30 (d, J = 6.4 Hz, 6 H,
Me), 1.31 (d, J = 6.0 Hz, 6 H, Me), 1.34 (d, J = 6.0 Hz, 6 H, Me),
4.34 (h, J = 6.4 Hz, 1 H), 4.39 (h, J = 6.0 Hz, 1 H), 4.44 (h, J =
6.0 Hz, 1 H), 6.60 (s, 1 H), 7.02 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.1 (q), 22.2 (q), 72.6 (d), 73.3 (d), 73.4 (d), 105.2 (s),
109.1 (d), 123.2 (d), 144.3 (s), 149.0 (s), 149.4 (s) ppm. MS (ESI-
TOF): m/z (%) = 353 (98) [MBr79], 354 (23) [MBr79 + 1], 355 (100)
[MBr81], 356 (21) [MBr81 + 1]. HRMS: calcd. for C15H23O3NaBr:
353.0728; found 353.0723.
Experimental Section
Reactants and solvents were purified according to literature pro-
cedures.[22] HPLC/MS spectra were recorded with a Waters Al-
liance LC/MS System consisting of a Waters ZQ mass detector, a
photodiode array detector, and an Alliance HPLC system equipped
with an XTerra C18 column (150ϫ4.6 mm, 5 µm). 1H and 13C
NMR spectra were recorded with a Varian Mercury 400 MHz and
a Gemini 200 MHz spectrometer. The multiplicity of the carbon
atoms was assigned through DEPT and gHSQC experiments and
typical abbreviations for off-resonance decoupling are used: (s) sin-
glet, (d) doublet, and (q) quartet. The same abbreviations were used
for the multiplicity of signals in the 1H NMR spectra, as well as
(h) heptet and (br. s) broad singlet. Spectra were referenced to ap-
propriate residual solvent peaks ([D6]DMSO or CDCl3). IR spectra
were obtained on a Thermo Nicolet FT-IR spectrometer. HRMS:
were recorded with a Bruker Autoflex high-resolution mass spec-
trometer.
1-Bromo-2,5-dimethoxy-4-isopropyloxybenzene (2e):[14e,24] Starting
from 1,4-dimethoxy-2-isopropyloxybenzene (1.22 g, 6.21 mmol), 2e
(1.63 g, 5.92 mmol, 95%) was obtained as a yellowish oil using
THF as solvent. IR (film): ν = 2975, 2934, 1501, 1382, 1201 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 1.33 (d, JH,H = 6.0 Hz, 6 H,
3
Me), 3.78 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 4.48 (h, JH,H
=
6.0 Hz, 1 H), 6.57 (s, 1 H), 7.03 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.0 (q, Me), 56.7 (q, OMe), 57.1 (q, OMe), 72.4 (d),
102.1 (s), 103.7 (d), 117.3 (d), 145.5 (s), 147.2 (s), 150.2 (s) ppm.
MS (ESI-TOF): m/z (%) = 274 (95) [MBr79], 275 (19) [MBr79 + 1],
276 (79) [MBr81], 305 (5) [MBr81 + 1]. HRMS: calcd. for
C11H16O3Br: 274.0205; found 274.0277.
General Procedure for the Bromination Process: Solid NBS
(1 mmol) was added to a cooled solution of the aromatic com-
pound (1 mmol) in THF or DMF (5 mL) and the reaction mixture
was stirred at the indicated temperature until complete consump-
tion of the starting material. The mixture was allowed to reach
room temperature and the solvent evaporated under reduced pres-
sure. The resulting residue was taken up in EtOAc, filtered through
a pad of neutral alumina, and dried. Pure products were charac-
terized as detailed below.
1-Bromo-2,4-bis(isopropyloxy)-5-methoxybenzene (2f): Starting
from 1,3-bis(isopropyloxy)-4-methoxybenzene (1.56 g, 6.96 mmol),
2f (2.11 g, 6.95 mmol, quant) was obtained as a yellowish oil using
THF as solvent. IR (film): ν = 2977, 2934, 1496, 1386, 1211,
˜
3
825 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.34 (d, JH,H
=
3
6.4 Hz, 6 H, Me), 1.35 (d, JH,H = 6.0 Hz, 6 H, Me), 3.80 (s, 3 H,
OMe), 4.44 (h, 3JH,H = 6.0 Hz, 1 H), 4.46 (h, 3JH,H = 6.4 Hz, 1 H),
6.60 (s, 1 H), 7.02 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 22.2 (q), 22.4 (q), 56.8 (q), 72.4 (d), 74.2 (d), 105.4 (s), 108.7 (d),
117.0 (d), 144.4 (s), 147.2 (s), 148.8 (s) ppm. MS (ESI-TOF): m/z
(%) = 302 (92) [MBr79], 303 (57) [MBr79 + 1], 304 (83) [MBr81],
305 (47) [MBr81 + 1]. HRMS: calcd. for C13H20O3Br: 303.0596;
found 303.0590.
4-Bromo-1,2,3-trihydroxybenzene (2a):[7a] Starting from 1,2,3-trihy-
droxybenzene (3.86 g, 30.3 mmol), 2a (5.69 g, 27.8 mmol, 92%) was
obtained as a yellowish solid using THF as solvent. IR (film): ν =
˜
3116, 2962, 1401, 1261, 1094, 1021, 800 cm–1. 1H NMR (400 MHz,
3
3
[D6]DMSO): δ = 6.26 (d, JH,H = 8.7 Hz, 1 H), 6.72 (d, JH,H
=
8.7 Hz, 1 H), 6.83 (s, 1 H, OH), 7.09 (s, 1 H, OH), 7.34 (s, 1 H,
OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 99.5 (s), 108.0
(d), 121.4 (d), 134.4 (s), 143.4 (s), 145.5 (s) ppm. MS (ESI-TOF):
m/z (%) = 203 (100) [MBr79], 205 (97) [MBr81]. HRMS: calcd. for
C6H4O3Br: 202.9349; found 202.9346.
6-Bromo-2,3-dimethoxyphenol (2b):[23] Starting from 2,3-dimeth-
oxyphenol (3.36 g, 21.8 mmol), 2b (3.57 g, 15.3 mmol, 70%) was
4-Bromo-5-isopropyloxy-2-methoxyphenyl tert-Butyl Carbonate
(2g): Starting from 5-isopropyloxy-2-methoxyphenyl tert-butyl car-
bonate (0.312 g, 1.11 mmol), 2g (0.400 g, 1.11 mmol, quant) was
obtained as a yellowish oil using THF as solvent. IR (film): ν =
˜
2978, 2935, 1764, 1502, 1139 cm–1. 1H NMR (200 MHz, CDCl3):
3
δ = 1.32 (d, JH,H = 6.0 Hz, 6 H, Me), 1.52 (s, 9 H, Me), 3.78 (s, 3
3
H, OMe), 4.37 (h, JH,H = 6.0 Hz, 1 H), 6.76 (s, 1 H), 7.12 (s, 1
obtained as a yellowish oil using THF as solvent. IR (film): ν =
˜
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.1 (q), 27.6 (q), 56.6
(q), 73.5 (d), 83.6 (s), 110.5 (s), 111.9 (d), 116.6 (s), 117.2 (d), 139.5
(s), 145.9 (s), 148.3 (s) ppm. MS (ESI-TOF): m/z (%) = 383 (100)
3440, 2941, 1466, 1429, 1204, 1168, 1089 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.83 (s, 3 H, OMe), 3.89 (s, 3 H, OMe),
3
3
6.13 (s, 1 H, OH), 6.40 (d, JH,H = 8.8 Hz, 1 H), 7.13 (d, JH,H
=
[MBr79], 384 (11) [MBr79 + 1], 385 (97) [MBr81], 386 (9) [MBr81
1]. HRMS: calcd. for C8H9O3NaBr: 383.0470; found 383.0465.
+
8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 56.0 (q,
OMe), 61.1 (q, OMe), 100.2 (s), 105.1 (d), 126.7 (d), 136.3 (s), 146.7
(s), 151.9 (s) ppm. MS (ESI-TOF): m/z (%) = 255 (100) [MBr79Na],
257 (98) [MBr81]. HRMS: calcd. for C8H9O3NaBr 254.9627; found
254.9620.
Supporting Information (see also the footnote on the first page of
this article): NMR spectra of the products.
1-Bromo-2,4,5-trihydroxybenzene (2c): Starting from 1,2,4-trihy-
droxybenzene (300 mg, 2.4 mmol), 2c (83 mg, 0.4 mmol, 17%) was
Acknowledgments
obtained as a yellowish oil using THF as solvent. IR (film): ν =
˜
3334, 1457, 1289, 1133, 837 cm–1. 1H NMR (400 MHz, CDCl3, This work was partially supported by the Comisión Interministerial
25 °C): δ = 5.03 (br. s, OH), 5.36 (br. s, OH), 5.48 (br. s, OH), 6.97 de Ciencia y Tecnología (CICYT) (BQU 2003-00089), the Genera-
(s, 1 H), 7.16 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = litat de Catalunya, and the Barcelona Science Park. D. P. thanks
Eur. J. Org. Chem. 2007, 1921–1924
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1923

D. Pla, F. Albericio, M. Álvarez
FULL PAPER
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Received: November 6, 2006
Published Online: February 27, 2007
1924
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