An efficient route to pentasubstituted phenols

Article abstract of DOI:10.1002/ejoc.200500603

A simple and convenient three-step protocol for the synthesis of pentasubstituted tribromophenols based on the acid-catalyzed Grob-type fragmentation of the bicyclic ketone precursors 8a-e in high overall yield is described. The bicyclic ketones 8a-e were obtained in two steps starting from the Diels-Alder cycloadducts 5a-e of β-substituted vinyl acetates and tetrabromo-5,5-dimethoxycyclopentadiene. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500603

FULL PAPER
DOI: 10.1002/ejoc.200500603
An Efficient Route to Pentasubstituted Phenols
Faiz Ahmed Khan*[a] and Sumit Choudhury[a]
Keywords: Pentasubstituted phenols / Grob-type fragmentation / Cycloaddition / Rearrangement / Diels–Alder reaction
A simple and convenient three-step protocol for the synthesis
of pentasubstituted tribromophenols based on the acid-cata-
lyzed Grob-type fragmentation of the bicyclic ketone precur-
sors 8a–e in high overall yield is described. The bicyclic
ketones 8a–e were obtained in two steps starting from the
Diels–Alder cycloadducts 5a–e of β-substituted vinyl acetates
and tetrabromo-5,5-dimethoxycyclopentadiene.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
the synthesis of pentasubstituted phenols based on this
strategy.
Introduction
Phenolic derivatives are ubiquitous both as naturally oc-
curring molecules and as important industrial intermedi-
ates.[1] Brominated phenols have been reported to occur nat-
urally in some marine sediments. Recent studies revealed
the wide occurrence of bromophenols in marine algae
which are believed to be a possible source of such com-
pounds in fish that feed predominantly on ocean plants.[2]
Interestingly a large number of brominated phenols have
been detected in the blood of humans and wild animals as
well as in fish and their role in living systems has been the
subject of intense study.[3]
(1)
Results and Discussion
Although substituted phenols are conventionally pre-
pared from benzenoid precursors, numerous methods are
available to construct the benzene skeleton from acyclic pre-
cursors.[4] Substituted phenols have also been prepared
from cyclic six-membered dienones by rearrangement.[5]
Ring-opening followed by rearrangement of Diels–Alder
cycloadducts of substituted furans is another convenient
route to phenol derivatives.[6] Photochemical rearrangement
of bicyclo[3.1.0]hex-3-en-2-ones has been reported to lead
to substituted phenols.[7]
Recently we demonstrated the quantitative conversion of
1,4,5,6-tetrahalo-7,7-dimethoxybicyclo[2.2.1]hept-5-ene-2-
one (1) to the 2,3,4-trihalophenol derivative 2 [Equa-
tion (1)].[8] The bicyclic ketone precursor 1 was derived
from the Diels–Alder cycloadduct of vinyl acetate and tet-
rahalo-5,5-dimethoxycyclopentadiene by hydrolysis of the
initial adduct followed by oxidation.[8] It occurred to us that
a general methodology for the synthesis of alkyl- or aryl-
substituted tribromophenols could be developed if we suc-
ceed in placing an alkyl or aryl substituent at the C3 atom
in 1. We herein report an efficient three-step protocol for
To install an alkyl or aryl group at the C3 atom of 1, β-
substituted vinyl acetates were considered as potential pre-
cursors. A literature search revealed that the use of β-substi-
tuted vinyl acetates as dienophiles in Diels–Alder reactions
of tetrabromo-5,5-dimethoxycyclopentadiene remained un-
explored. We thought of evaluating the efficacy of this cy-
cloaddition reaction in order to obtain alkyl- or aryl-substi-
tuted bicyclic ketones, suitable precursors of the corre-
sponding 2,3,4-tribromophenol derivatives. The β-substi-
tuted vinyl acetates were prepared starting from aldehydes
3a–e, using known procedures,[9] to give a mixture of (Z)-
and (E)-4a–e (Scheme 1). The (Z)/(E) mixture of enol ace-
tates 4 (taken in excess) was subjected to Diels–Alder reac-
tion with tetrabromo-5,5-dimethoxycyclopentadiene in the
presence of catalytic amounts of hydroquinone (free-radical
scavenger) and epichlorohydrin (acid scavenger). The reac-
tion required 6–8 days at 140–150 °C in a sealed tube and
furnished a 68–75% yield of endo,endo adducts 5a–d. For
4e the yield was only 36% since the reaction was carried out
at 120 °C owing to decomposition at higher temperature
as indicated by the gradually increasing black color of the
reaction mixture. Note that only the (Z)-enol acetates 4a–e
reacted to furnish the endo,endo adducts 5a–e. The endo,exo
adducts 6 were not formed presumably as a result of unfa-
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur-208 016, India
Fax: +91-512-2597436
E-mail: faiz@iitk.ac.in
672
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 672–676

An Efficient Route to Pentasubstituted Phenols
FULL PAPER
vorable steric interactions between the R and OMe groups
of the diene in the transition state.
Having obtained the requisite cycloadducts 5a–e, our
next task was to convert them efficiently to substituted bicy-
clic ketones and finally to the tribromophenols. This
straightforward three-step sequence is depicted in
Scheme 2. The cycloadducts 5a–e were hydrolyzed em-
ploying K2CO3 in MeOH to furnish 90–99% yield of the
alcohols 7a–e. Oxidation of the secondary alcohol group
was accomplished in excellent yield using PDC in dichloro-
methane at room temperature to obtain the bicyclic ketones
8a–e.
Scheme 1. Synthesis of endo,endo adducts 5a–e.
Unambiguous structural proof for the formation of
1
endo,endo adducts 5a–e came from H NMR spectroscopy
(400 MHz). The coupling constants for C2-Hexo (Ha) with
C3-Hexo (Hb) and C3-Hendo (Hc) are quite diagnostic and
fall in the range of 8.0–8.3 Hz for Ha,b and 2.1–2.4 Hz for
Ha,c (Figure 1). Comparison of the observed coupling con-
stants of unsubstituted alcohols[8] with those of 5a–e, given
in Figure 1, clearly indicates that the R group is endo. An-
other characteristic feature is the chemical shifts of the Hb
and Hc protons. The endo proton (Hc) is shielded and ap-
pears at around 1.75 ppm. The observed chemical shift for
5a (2.75–2.71 ppm, Figure 1) provides support for the endo
assignment of the R group. Similarly, the C3-H chemical
shifts for 5b–e are consistent with this assignment (see Ex-
perimental Section).
Scheme 2. Synthesis of pentasubstituted tribromo phenols 9 from
Diels–Alder adducts 5.
For the final step, which involved Grob-type fragmenta-
tion of the C1–C7 bond, the reaction conditions were opti-
mized using bicyclic ketone 8c. Unlike the parent bicyclic
ketone 1, which underwent smooth fragmentation at room
temperature on standing and spontaneous cleavage at
90 °C,[8] the substituted 8c remained unchanged even after
heating in DMSO at 100 °C for two hours. The results of
optimization are shown in Table 1. When 50 mol-% of the
acid catalyst (PTSA) was used in DMSO, no change was
observed at room temperature nor at 130 °C (entries 2 and
3, Table 1). When the temperature was elevated to 150 °C,
the product 9c was formed in 86% yield. Toluene appeared
to be the solvent of choice, furnishing a near quantitative
yield of 9c in just 30 minutes with both 100 and 50 mol-%
of acid catalyst (entries 5 and 6, Table 1). Reducing the
amount of acid catalyst to 20 mol-% showed no beneficial
effects. Therefore, the conditions given in entry 6 of Table 1
(50 mol-% PTSA, 110–120 °C, toluene) were used for the
reactions of the ketones 8a–e.
The fragmentation product 9e, derived from bicyclic
ketone 8e, was converted into the corresponding methyl
ether 10 by treatment with MeI/K2CO3 [Equation (2)]. This
was done for the sake of purification and characterization
Figure 1. Comparison of the coupling constants and chemical
shifts of 5a with those of the parent alcohols.
Eur. J. Org. Chem. 2006, 672–676
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www.eurjoc.org
673

F. A. Khan, S. Choudhury
Product yield[a] [%]
FULL PAPER
Table 1. Grob-type fragmentation of 8c to give 9c.
Entry
Solvent
Temp. [°C]
Catalyst [mol-%]
Time
1
2
3
4
5
6
7
DMSO
DMSO
DMSO
DMSO
toluene
toluene
toluene
100
room temp.
130
–
2 h
2 h
1 h
6 h
30 min
30 min
12 h
no reaction
no reaction
no reaction
86
PTSA (50)
PTSA (50)
PTSA (50)
PTSA (100)
PTSA (50)
PTSA (20)
150
110–120
110–120
110–120
97
96
slow reaction[b]
[a] Isolated yield. [b] Little product was formed; unreacted starting material was the major component, as monitored by TLC.
which was purified by chromatography on a silica gel column using
ethyl acetate/hexane as the eluent to furnish the Diels–Alder cy-
cloadduct 5a.
since the polarity of 9e was such that it could not be cleanly
separated from impurities.
1,4,5,6-Tetrabromo-3-propyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-
2-yl Acetate (5a): Rf = 0.70 (5% EtOAc in hexane); yield: 2.494 g,
73 %; solid, m.p. 84–86 °C; unreacted diene recovered: 375 mg,
1
12%. H NMR (400 MHz, CDCl3): δ = 5.82 (d, J = 8.0 Hz, 1 H,
C2-Hexo), 3.56 (s, 3 H, OMe), 3.51 (s, 3 H, OMe), 2.75–2.71 (m, 1
H, C3-Hexo), 2.02 (s, 3 H, -OCOCH3), 1.51–1.46 (m, 1 H), 1.12–
1.09 (several m, 3 H), 0.81 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.1, 125.8, 123.4, 111.3, 78.5, 73.2, 71.5,
(2)
53.1, 52.3, 51.7, 26.1, 21.5, 20.5, 14.2 ppm. IR (KBr): ν = 2900,
˜
1720, 1560, 1420, 1350, 1200, 1160, 1120, 1080, 1040 cm–1.
We have established a simple and convenient three-step
protocol for the synthesis of pentasubstituted tribromo-
phenols based on a Grob-type fragmentation strategy. The
bicyclic ketone precursors 8a–e were acquired in high over-
all yield from the Diels–Alder cycloadducts 5a–e, formed
from β-substituted vinyl acetates and tetrabromo-5,5-di-
methoxycyclopentadiene, by hydrolysis followed by efficient
oxidation of the resulting secondary alcohols 7a–e. Both
alkyl as well as aryl substituents work equally well. The
Grob-type fragmentation of bicyclic ketone precursors 8a–
e was triggered in the presence of acid catalyst PTSA to
furnish near quantitative yields of the pentasubstituted trib-
romophenols 9a–e.
1,4,5,6-Tetrabromo-3-butyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
yl Acetate (5b): Rf = 0.70 (5% EtOAc in hexane); yield: 2.976 g,
75 % from tetrabromo-5,5-dimethoxycyclopentadiene (3.012 g,
6.82 mmol) and enol acetate (Z)/(E)-4b [9 mL; (Z)/(E) Ϸ 36:64];
1
solid, m.p. 110 °C. H NMR (400 MHz, CDCl3): δ = 5.89 (d, J =
8.3 Hz, 1 H, C2-Hexo), 3.63 (s, 3 H, OMe), 3.58 (s, 3 H, OMe),
2.77–2.76 (m, 1 H, C3-Hexo), 2.09 (s, 3 H, -OCOCH3), 1.57–1.55
(m, 2 H), 1.32–1.07 (several m, 4 H), 0.86 (t, J = 7.1, Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.1, 125.8, 123.4, 111.3, 78.5,
73.2, 71.5, 52.5, 52.1, 51.8, 30.4, 23.6, 22.7, 20.5, 13.9 ppm. IR
(KBr): ν = 2900, 1740, 1560, 1420, 1360, 1280, 1200 cm–1
.
˜
C15H20O4Br4 (583.94): calcd. C 30.85, H 3.45; found C 31.01, H
3.68.
1,4,5,6-Tetrabromo-3-pentyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
yl Acetate (5c): Rf = 0.70 (5% EtOAc in hexane); yield: 1.176 g,
68 % from tetrabromo-5,5-dimethoxycyclopentadiene (1.278 g,
2.89 mmol) and enol acetate (Z)/(E)-4c [3.6 mL; (Z)/(E) Ϸ 35:65];
viscous liquid. 1H NMR (400 MHz, CDCl3): δ = 5.82 (d, J =
8.0 Hz, 1 H, C2-Hexo), 3.56 (s, 3 H, OMe), 3.51 (s, 3 H, OMe),
2.73–2.68 (m, 1 H, C3-Hexo), 2.02 (s, 3 H, -OCOCH3), 1.5–1.45 (m,
1 H), 1.21–1.04 (m, 7 H), 0.80 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.9, 125.7, 123.3, 111.2, 78.4, 73.1, 71.4,
Experimental Section
General Information: Melting points are uncorrected. IR spectra
were recorded in the form of KBr pellets (solids) or as thin films
1
(liquids). H NMR and proton decoupled 13C NMR spectra were
recorded at 400 and 100 MHz, respectively. NMR data are reported
as follows: multiplicity [s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet], coupling constant(s) in Hz, integration,
assignment. Samples for NMR analysis were prepared in CDCl3
and tetramethylsilane was used as the internal standard. Column
chromatography was performed using silica gel (Acme: 100–200
mesh) with ethyl acetate/hexane used as eluent. The mixtures of
enol acetates, (Z)/(E)-4a,[10a] 4b,[10b,10c] 4c,[10d] 4d[10e] and 4e,[10b,10e]
were prepared according to the literature procedure.[9]
53.0, 52.4, 51.7, 31.8, 27.9, 23.9, 22.3, 20.4, 13.9 ppm. IR (neat): ν
˜
= 2900, 1740, 1540, 1440, 1360, 1180 cm–1.
1,4,5,6-Tetrabromo-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
yl Acetate (5d): Rf = 0.70 (5% EtOAc in hexane); yield: 2.702 g,
70 % from tetrabromo-5,5-dimethoxycyclopentadiene (2.797 g,
6.33 mmol) and enol acetate (Z)/(E)-4d [9 mL; (Z)/(E) Ϸ 32:68];
viscous liquid. 1H NMR (400 MHz, CDCl3): δ = 5.88 (d, J =
General Procedure for the Preparation of Diels–Alder Adducts 5a–
e: A mixture of tetrabromo-5,5-dimethoxycyclopentadiene (3.016 g,
6.82 mmol), excess enol acetate (Z)/(E)-4a [9 mL; (Z)/(E) Ϸ 38:62], 8.3 Hz, 1 H, C2-Hexo), 3.63 (s, 3 H, OMe), 3.58 (s, 3 H, OMe),
catalytic amounts of hydroquinone (5 mg) and epichlorohydrin
(0.5 mL) in dry benzene (10 mL) was heated at 140–150 °C in a
sealed tube under an inert atmosphere for 6–8 days. The solvent
was evaporated under reduced pressure. The reaction mixture was
then distilled (2 mbar, 110 °C) using a kugelrohr apparatus to re-
move the excess enol acetate 4a to furnish a deep-red oily mass
2.79–2.75 (m, 1 H, C3-Hexo), 2.09 (s, 3 H, -OCOCH3), 1.57–1.53
(m, 1 H), 1.28–1.11 (several m, 9 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.9, 125.7, 123.3, 111.2, 78.4,
73.1, 71.4, 53.0, 52.4, 51.6, 31.5, 29.3, 28.2, 23.9, 22.5, 20.4,
13.9 ppm. IR (neat): ν = 2900, 1760, 1580, 1460, 1360, 1220,
˜
1180 cm–1.
674
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Eur. J. Org. Chem. 2006, 672–676

An Efficient Route to Pentasubstituted Phenols
FULL PAPER
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en- 13C NMR (100 MHz, CDCl3): δ = 125.9, 122.7, 111.4, 79.6, 74.8,
2-yl Acetate (5e): Rf = 0.70 (10% EtOAc in hexane); yield: 0.768 g, 73.8, 53.0, 52.6, 51.6, 31.7, 29.4, 29.2, 23.8, 22.6, 14.1 ppm. IR
36 % from tetrabromo-5,5-dimethoxycyclopentadiene (2.035 g, (neat): ν = 3500 (OH), 2900, 1560, 1460, 1180, 1160, 1100,
˜
4.60 mmol) and enol acetate (Z)/(E)-4e [1.4 mL; (Z)/(E) Ϸ 35:65];
unreacted diene recovered: 463 mg, 23%; solid, m.p. 134 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.29–7.26 (m, 3 H), 7.12–7.09 (m, 2
H), 5.8 (d, J = 8.1 Hz, 1 H, C2-Hexo), 4.07 (d, J = 8.0 Hz, 1 H,
C3-Hexo), 3.72 (s, 3 H, OMe), 3.63 (s, 3 H, OMe), 1.83 (s, 3 H,
-OCOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.5, 131.8,
131.4, 128.2, 127.7, 127.3, 124.2, 111.9, 81.1, 73.6, 70.9, 58.6, 53.3,
960 cm–1.
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-
2-ol (7e): Rf = 0.50 (10% EtOAc in hexane); yield: 576 mg, 90%
from 5e (683 mg, 1.13 mmol); solid, m.p. 106 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.34–7.29 (m, 3 H), 7.25–7.21 (m, 2 H),
4.84 (d, J = 7.8 Hz, 1 H, C2-Hexo), 3.89 (d, J = 8.0 Hz, 1 H, C3-
H
exo), 3.69 (s, 3 H, OMe), 3.62 (s, 3 H, OMe), 1.97 (br. s, 1 H,
51.9, 20.4 ppm. IR (KBr): ν = 2900, 1740, 1560, 1480, 1440, 1360,
D2O exchangeable) ppm. 13C NMR (100 MHz, CDCl3): δ = 132.4,
˜
1220, 1180, 1060, 980, 860 cm–1. C17H16Br4O4 (603.93): calcd. C
33.77, H 2.65; found C 33.85, H 2.54.
131.4, 128.2, 127.8, 126.6, 124.3, 111.7, 80.6, 74.3, 74.1, 58.8, 53.3,
51.8 ppm. IR (KBr): ν = 3500, 2900, 1560, 1490, 1440, 1400, 1180,
˜
1100, 1020, 960, 880, 800 cm–1. C15H14Br4O3 (561.89): calcd. C
32.03, H 2.49; found C 31.89, H 2.16.
General Procedure for the Preparation of Alcohols 7a–e: K2CO3
(460 mg, 3.33 mmol) was added to a solution of the cycloadduct
5a (1.637 g, 3.22 mmol) in MeOH (15 mL) and the mixture was
stirred at room temperature for 30 min. After complete consump-
tion of the starting material (TLC monitoring) the solvent was
evaporated under reduced pressure, water (20 mL) was added to
the residue and the aqueous layer was extracted with EtOAc
(3×20 mL). The combined organic layers were then washed with
brine and dried with anhydrous Na2SO4. The solvent was evapo-
rated under reduced pressure. The residue was purified by
chromatography on silica gel using ethyl acetate/hexane as the elu-
ent to afford the alcohol 7a.
General Procedure for the Preparation of Bicyclic Ketones 8a–e:
CrO3 (1.669 g, 16.69 mmol) was added to a solution of pyridine
(2.637 g, 33.38 mmol) in CH2Cl2 (50 mL) and the mixture was
stirred at room temperature for 30 min. A solution of the alcohol
7a (1.307 g, 2.475 mmol) in CH2Cl2 (50 mL) was added to this deep
brown colored mixture and the mixture was stirred at room tem-
perature for 40 h. The inorganic solids were then filtered off
through a small silica gel pad and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy using ethyl acetate/hexane as the eluent to furnish the corre-
sponding bicyclic ketone 8a.
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-
2-ol (7a): Rf = 0.60 (5% EtOAc in hexane); yield: 1.583 g, 93%;
solid, m.p. 110–112 °C. H NMR (400 MHz, CDCl3): δ = 4.64 (d,
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-
2-one (8a): Rf = 0.80 (5% EtOAc in hexane); 1.237 g, 95%; solid,
m.p. 82–84 °C. 1H NMR (400 MHz, CDCl3): δ = 3.63 (s, 3 H,
OMe), 3.59 (s, 3 H, OMe), 2.68 (dd, J = 4.8, 8.4 Hz, 1 H, C3-Hexo),
1.72–1.38 (several m, 4 H), 0.92 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 196.7, 130.9, 118.9, 114.4, 78.5, 70.7, 53.4,
1
J = 8.0 Hz, 1 H, C2-Hexo), 3.58 (s, 3 H, OMe), 3.55 (s, 3 H, OMe),
2.66–2.61 (m, 1 H, C3-Hexo), 1.86 (br. s, 1 H, D2O exchangeable),
1.53–1.44 (m, 2 H), 1.35–1.24 (m, 2 H), 0.91 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 125.9, 122.7, 111.4,
79.6, 74.8, 73.8, 53.0, 52.4, 51.6, 25.9, 22.4, 14.2 ppm. IR (KBr):
51.8, 51.9, 29.9, 21.4, 13.9 ppm. IR (KBr): ν = 2900, 1750 (C=O),
˜
1550, 1440, 1160, 1100, 960 cm–1.
ν = 3500 (OH), 2900, 1550, 1440, 1240, 1160, 1140, 1080, 1040,
˜
960 cm–1.
1,4,5,6-Tetrabromo-3-butyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
one (8b): Rf = 0.80 (5% EtOAc in hexane); yield: 1.825 g, 91% from
7b (2.012 g, 3.7 mmol); solid, m.p. 76 °C. 1H NMR (400 MHz,
CDCl3): δ = 3.62 (s, 3 H, OMe), 3.59 (s, 3 H, OMe), 2.67 (dd, J =
4.5, 8.2 Hz, 1 H, C3-Hexo), 1.72–1.27 (several m, 6 H), 0.89 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.7, 130.9,
118.9, 114.4, 78.5, 70.8, 53.4, 52.1, 51.9, 30.2, 27.6, 22.5, 13.8 ppm.
1,4,5,6-Tetrabromo-3-butyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
ol (7b): Rf = 0.60 (5% EtOAc in hexane); yield: 2.470 g, 92% from
5b (2.902 g, 4.96 mmol); solid, m.p. 76–78 °C. 1H NMR (400 MHz,
CDCl3): δ = 4.59 (d, J = 7.8 Hz, 1 H, C2-Hexo), 3.53 (s, 3 H, OMe),
3.51 (s, 3 H, OMe), 2.59–2.55 (m, 1 H, C3-Hexo), 1.77 (br. s, 1 H,
D2O exchangeable), 1.50–1.20 (several m, 6 H), 0.83 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 125.9, 122.7, 111.3,
79.6, 74.7, 73.8, 53.0, 52.5, 51.6, 31.4, 23.4, 22.7, 13.9 ppm. IR
IR (KBr): ν = 2900, 1760 (C=O), 1560, 1480, 1200, 1140, 1120,
˜
980, 880 cm–1. C13H16O3Br4 (539.88): calcd. C 28.92, H 2.99; found
C 29.07, H 3.15.
(KBr): ν = 3450 (OH), 2900, 1560, 1440, 1160, 1140, 1060, 1000,
˜
960 cm–1. C13H18Br4O3 (541.90): calcd. C 28.81, H 3.35; found C
29.07, H 3.52.
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-
one (8c): Rf = 0.80 (5% EtOAc in hexane); yield: 730 mg, 95%
from 7c (765 mg, 1.376 mmol); viscous liquid. 1H NMR (400 MHz,
CDCl3): δ = 3.58 (s, 3 H, OMe), 3.55 (s, 3 H, OMe), 2.63 (dd, J =
4.9, 8.5 Hz, 1 H, C3-Hexo), 1.67–1.49 (m, 1 H), 1.41–1.19 (several
m, 7 H), 0.83 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.6, 130.9, 118.9, 114.4, 78.5, 70.8, 53.4, 52.1, 51.9,
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-
ol (7c): Rf = 0.60 (5% EtOAc in hexane); yield: 979 mg, 99% from
5c (1.058 g, 1.77 mmol); viscous liquid. 1H NMR (400 MHz,
CDCl3): δ = 4.68 (d, J = 8.0 Hz, 1 H, C2-Hexo), 3.60 (s, 3 H, OMe),
3.57 (s, 3 H, OMe), 2.67–2.62 (m, 1 H, C3-Hexo), 1.95 (br. s, 1 H,
D2O exchangeable), 1.66–1.43 (m, 2 H), 1.37–1.26 (m, 6 H), 0.88
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 125.9,
122.7, 111.3, 79.5, 74.7, 73.8, 52.9, 52.6, 51.5, 31.8, 28.9, 23.7, 22.5,
31.5, 27.9, 27.8, 22.3, 13.9 ppm. IR (neat): ν = 2900, 1760, 1550,
˜
1440, 1160, 1100, 960, 860 cm–1
1,4,5,6-Tetrabromo-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
14.0 ppm. IR (neat): ν = 3400, 2900, 1560, 1440, 1180, 1140 cm–1.
˜
one (8d): Rf = 0.80 (5% EtOAc in hexane); yield: 1.932 g, 90%
1
1,4,5,6-Tetrabromo-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-
ol (7d): Rf = 0.60 (5% EtOAc in hexane); yield: 2.262 g, 91% from
5d (2.663 g, 4.35 mmol); viscous liquid. 1H NMR (400 MHz,
CDCl3): δ = 4.59 (d, J = 8.1 Hz, 1 H, C2-Hexo), 3.53 (s, 3 H, OMe),
3.51 (s, 3 H, OMe), 2.60–2.55 (m, 1 H, C3-Hexo), 1.84 (br. s, 1 H,
D2O exchangeable), 1.52–1.47 (m, 1 H), 1.41–1.37 (m, 1 H), 1.29–
1.27 (m, 1 H), 1.24–1.21 (m, 7 H), 0.81 (t, J = 6.8 Hz, 3 H) ppm.
from 7d (2.161 g, 3.80 mmol); viscous liquid. H NMR (400 MHz,
CDCl3): δ = 3.58 (s, 3 H, OMe), 3.55 (s, 3 H, OMe), 2.63 (dd, J =
4.8, 8.4 Hz, 1 H, C3-Hexo), 1.63–1.22 (several m, 10 H), 0.82 (t, J
= 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.7,
130.9, 118.9, 114.4, 78.5, 70.8, 53.4, 52.1, 51.9, 31.5, 29.0, 28.1,
27.9, 22.5, 14.0 ppm. IR (neat): ν = 2900, 1760 (C=O), 1560, 1440,
˜
1180, 960, 860 cm–1.
Eur. J. Org. Chem. 2006, 672–676
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
675

F. A. Khan, S. Choudhury
1,4,5,6-Tetrabromo-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en- converted into the corresponding methyl ether for characterization
FULL PAPER
2-one (8e): Rf = 0.80 (10% EtOAc in hexane); yield: 284 mg, 87%
purposes as follows. Crude 9e was dissolved in dry acetone
(1.5 mL) and anhydrous K2CO3 (9 mg, 0.068 mmol) followed by
from 7e (327 mg, 0.582 mmol); solid, m.p. 147–148 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.27–7.24 (m, 3 H), 6.92–6.90 (m, 2 H), MeI (13 mg, 0.094 mmol) were added to this solution. The reaction
4.0 (s, 1 H, C3-Hexo), 3.66 (s, 3 H, OMe), 3.64 (s, 3 H, OMe) ppm. mixture was then stirred at room temperature for 4 h. After the
13C NMR (100 MHz, CDCl3): δ = 194.5, 131.9, 131.8, 130.0, 128.5, reaction was complete, the reaction mixture was diluted with water
128.4, 118.3, 113.9, 78.9, 71.9, 57.6, 53.6, 52.2 ppm. IR (KBr): ν =
(2 mL) and the aqueous layer was extracted with EtOAc
(3×10 mL). The combined organic layers were washed with brine
and dried with anhydrous Na2SO4. The solvent was concentrated in
vacuo to furnish a residue which was purified by silica gel column
chromatography using ethyl acetate/hexane as the eluent to afford
the methyl ether 10 (17 mg, 85%, for two steps) as a white crystal-
˜
2900, 1750 (C=O), 1550, 1480, 1440, 1170, 1100, 960, 860 cm–1.
General Procedure for the Preparation of Pentasubstituted Tri-
bromophenols 9a–e: p-Toluenesulfonic acid monohydrate, PTSA
(284 mg, 1.49 mmol), was added to a solution of the bicyclic ketone
8a (1.565 g, 2.97 mmol) in toluene (10 mL) and the reaction mix-
ture was refluxed at 110–120 °C for 30 min. After the reaction was
complete (TLC monitoring), the reaction mixture was diluted with
water (10 mL) and the aqueous layer was extracted with EtOAc
(3×20 mL). The combined organic layers were washed with brine
and dried with anhydrous Na2SO4. The solvent was concentrated in
vacuo to furnish a residue which was purified by silica gel column
chromatography to afford the phenol derivative 9a.
1
line solid, m.p. 130–132 °C, Rf = 0.80 (10% EtOAc in hexane). H
NMR (400 MHz, CDCl3): δ = 7.39–7.24 (m, 5 H), 3.55 (s, 3 H,
OMe), 3.37 (s, 3 H, -OMe) ppm. 13C NMR (100 MHz, CDCl3): δ
= 166.6, 155.2, 137.9, 134.4, 133.8, 129.2, 128.6, 128.5, 128.2, 123.9,
117.3, 60.7, 52.6 ppm. IR (KBr): ν = 1720 (C=O), 1420, 1340, 1260,
˜
1180, 1150, 1000, 960, 900, 840, 800 cm–1. C15H11Br3O3 (478.96):
calcd. C 37.58, H 2.29; found C 37.48, H 2.26.
Methyl 2,3,4-Tribromo-5-hydroxy-6-propylbenzoate (9a): Rf = 0.70
(5% EtOAc in hexane); yield: 1.234 g, 96%; solid, m.p. 118–120 °C.
1H NMR (400 MHz, CDCl3): δ = 5.83 (br. s, 1 H, D2O exchangea-
ble), 3.92 (s, 3 H, OMe), 2.51 (t, J = 7.9 Hz, 2 H), 1.60–1.53 (m, 2
H), 0.92 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 167.3, 150.9, 137.7, 127.7, 124.8, 115.3, 112.3, 52.8, 31.6, 22.5,
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi for financial assistance. F. A. K. acknowledges the DST for
a Swarnajayanti Fellowship. S. C. thanks the CSIR for a fellowship.
14.2 ppm. IR (KBr): ν = 3300 (OH), 2900, 1700 (C=O), 1540, 1400,
˜
1360, 1260, 1220, 1160, 1120, 1060 cm–1.
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Methyl 2,3,4-Tribromo-6-butyl-5-hydroxybenzoate (9b): Rf = 0.70
(5 % EtOAc in hexane); yield: 1.058 g, 98 % from 8b (1.303 g,
2.40 mmol); solid, m.p. 82 °C. 1H NMR (400 MHz, CDCl3): δ =
5.81 (br. s, 1 H, D2O exchangeable), 3.92 (s, 3 H, -COOMe), 2.53
(t, J = 7.5 Hz, 2 H), 1.54–1.47 (m, 2 H), 1.36–1.31 (m, 2 H), 0.87
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.3,
150.8, 137.6, 127.9, 124.7, 115.3, 112.3, 52.8, 31.3, 29.3, 22.8,
13.7 ppm. IR (KBr): ν = 3200 (OH), 2900, 1700 (C=O), 1540, 1450,
˜
1430, 1410, 1380, 1280, 1210, 1170, 1040, 980 cm–1. C12H13Br3O3
(444.95): calcd. C 32.39, H 2.95; found C 32.19, H 3.09.
Methyl 2,3,4-Tribromo-5-hydroxy-6-pentylbenzoate (9c): Rf = 0.70
(5 % EtOAc in hexane); yield: 556 mg, 96 % from 8c (700 mg,
1.263 mmol); solid, m.p. 92–94 °C. 1H NMR (400 MHz, CDCl3): δ
= 5.75 (br. s, 1 H, D2O exchangeable), 3.87 (s, 3 H, OMe), 2.48 (t,
J = 8.1 Hz, 2 H), 1.49–1.23 (several m, 6 H), 0.82 (t, J = 7.0 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.3, 150.8, 137.6,
127.9, 124.7, 115.3, 112.3, 52.8, 31.9, 29.6, 28.9, 22.3, 13.9 ppm. IR
(KBr): ν = 3200 (OH), 2900, 1700 (C=O), 1540, 1420, 1400, 1360,
˜
1280, 1200, 1140, 1080 cm–1.
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Received: August 8, 2005
Methyl 2,3,4-Tribromo-6-hexyl-5-hydroxybenzoate (9d): Rf = 0.70
(5 % EtOAc in hexane); yield: 1.434 g, 95 % from 8d (1.812 g,
3.19 mmol); viscous liquid. H NMR (400 MHz, CDCl3): δ = 5.77
(br. s, 1 H, D2O exchangeable), 3.87 (s, 3 H, OMe), 2.48 (t, J =
8.0 Hz, 2 H), 1.51–1.43 (m, 2 H), 1.28–1.19 (m, 6 H), 0.81 (t, J =
6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.3, 150.8,
137.6, 127.9, 124.7, 115.3, 112.3, 52.8, 31.4, 29.6, 29.4, 29.1, 22.5,
1
14.0 ppm. IR (neat): ν = 3400 (OH), 2980, 1710 (C=O), 1530, 1420,
˜
1400, 1360, 1260, 1200, 1140, 1080, 1000, 920 cm–1.
Methyl 2,3,4-Tribromo-5-methoxy-6-phenylbenzoate (10): The reac-
tion was carried out as described in the general procedure and then
the crude 9e [Ͼ90%, from 8e (24 mg, 0.043 mmol)] was directly
Published Online: November 30, 2005
676
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 672–676