Synthesis of phloroglucinol monoaryl ethers

Article abstract of DOI:10.1055/s-0031-1290768

A variety of novel functionalized phloroglucinol monoaryl ethers have been synthesized using a two-step procedure. Target ethers were synthesized by coupling electron-deficient aryl fluorides with 3,5-dimethoxyphenol via nucleophilic aromatic substitution (S_NAr) in N-methylpyrrolidone and cesium carbonate. Subsequent boron tribromide-mediated demethylation gave a series of phloroglucinol monoaryl ethers in good overall yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290768

1208▌
PAPER
paper
Synthesis of Phloroglucinol Monoaryl Ethers
Synthesis of Phloroglucinol Monoaryl Ethers
Alexander M. Sherwood, David M. Pond, Mark L. Trudell*
Department of Chemistry, University of New Orleans,, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-Mail: mtrudell@uno.edu
Received: 13.01.2012; Accepted after revision: 21.02.2012
(3). Unfortunately, the direct arylation of 3 proved to be
less straightforward. The uncatalyzed conditions led to a
complex mixture of mono- and diaryl ethers as well as an
intractable mixture of C-arylation products. In addition,
Abstract: A variety of novel functionalized phloroglucinol mono-
aryl ethers have been synthesized using a two-step procedure. Tar-
get ethers were synthesized by coupling electron-deficient aryl
fluorides with 3,5-dimethoxyphenol via nucleophilic aromatic sub-
stitution (SNAr) in N-methylpyrrolidone and cesium carbonate. the removal of the excess phloroglucinol made the isola-
Subsequent boron tribromide-mediated demethylation gave a series
of phloroglucinol monoaryl ethers in good overall yields.
tion and purification of the coupling products cumber-
some and tedious.
Key words: arylation, ethers, nucleophilic aromatic substitution,
phenols, phloroglucinol
KOH
+
NMP
65 °C
F3C
Cl
HO
OH
F C
3
O
OH
(excess)
OH
CN
CN
In our efforts to synthesize novel analogues of the canna-
binoid partial agonist BAY 59-3074 (Figure 1), we have
developed a simple, catalyst-free procedure for the syn-
thesis of phloroglucinol monoaryl ethers. To our knowl-
edge, no formal report exists describing the synthesis of
phloroglucinol monoaryl ethers. The structures presented
here represent a relatively unexplored substructure of
compounds that may be useful building blocks in a variety
of applications.
1 (79%)
KOH
intractable mixture
+
NMP
65 °C
F3C
F
HO
OH
(excess)
CN
2
3
Scheme 1 Attempted direct arylation of phloroglucinol
O
In light of these results, we sought to develop a stoichio-
metric uncatalyzed method for the preparation of the de-
sired phloroglucinol monoaryl ethers. To this end, a two-
step process was envisaged that would involve initial aryl
ether formation via coupling a substituted aryl fluoride 4
with a protected phloroglucinol derivative followed by a
deprotection step to give the phloroglucinol monoaryl
ether (Scheme 2). 3,5-Dimethoxyphenol (5) seemed to be
a particularly amenable substrate for the uncatalyzed cou-
pling reaction due to electron-donating methoxy groups
that would activate the phenol toward SNAr nucleophilic
addition. The methyl ethers could then be readily removed
to furnish the phloroglucinol derivative. Cesium carbon-
ate was selected as the base for the reaction since it has
been widely used for the generation of phenoxide salts in
S
CF3
F3C
O
O
O
CN
Figure 1 Cannabinoid partial agonist BAY59-3074
Several methods have been reported for the preparation of
diaryl ethers, many of which rely on copper catalysts.1,2
We have chosen to proceed through uncatalyzed SNAr
promoting conditions for the sake of simplicity. Reactions
that proceed via an SNAr mechanism represent one of the
more attractive methods for diaryl ether synthesis due to
mild reaction conditions typically employed to affect the
desired coupling.3,4 The preparation of the diaryl ether
precursor 1 to BAY 59-3074 was achieved via uncata-
lyzed conditions in good yield in N-methylpyrrolidone
(NMP) using KOH as a base (Scheme 1).5 Other reports
have also demonstrated NMP to be advantageous in the
synthesis of diaryl ethers.6 As a solvent, NMP is ideal for
these uncatalyzed coupling reactions since it possesses a
high boiling point (203 °C) and large dielectric constant
(32.2). Based upon these results we initially explored the
uncatalyzed conditions developed for 1 for the aryl ether
coupling reaction of aryl fluoride 2 with phloroglucinol
OMe
OMe
Z
Y
Z
Y
Cs2CO3
NMP
+
F
O
OMe
HO
OMe
X
4
X
5
6–13
OH
1) BBr3, CH2Cl2, 0 °C
2) H2O, 0 °C
Z
Y
O
OH
X
SYNTHESIS 42170012, 44,81208–1212
14–21
Advanced online publication: 27.03.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290768; Art ID: SS-2012-M0045-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Two-step synthesis of phloroglucinol monoaryl ethers

PAPER
Synthesis of Phloroglucinol Monoaryl Ethers
1209
diaryl ether coupling reactions due to its functional group The dimethoxy diaryl ethers 6–13 were converted into the
tolerance and good solubility in organic solvents.7–10
phloroglucinol derivatives 14–21 using boron tribromide.
This demethylation process has been well covered in the
literature.13,14 However, it is worth noting that special care
must be taken with the quench/hydrolysis procedure in or-
der to achieve high yields. It was found that slowly drip-
ping the reaction mixture into an excess of stirred cold
water produced the best results. All of the reactions pro-
ceeded cleanly and in high yield (>89%) with the excep-
tion of the nitrile 6. The demethylation step gave a
mixture of side products that made it necessary to purify
the phloroglucinol derivative 14 (Table 2, entry 1) by col-
umn chromatography. All other compounds were isolated
in sufficient purity for subsequent use directly from the
workup with no chromatography.
As summarized in Table 1 the uncatalyzed coupling reac-
tions of substituted aryl fluorides 4 with 5 gave the corre-
sponding diaryl ethers 6–13 in good to high yields. The
coupling reactions presented here support an SNAr mech-
anism. Substrates that possessed strong activating groups
such as nitrile (entries 1 and 7) and nitro (entry 8) gave
nearly quantitative yields, presumably via formation of an
intermediate Meisenheimer complex.3 However, weaker
activating groups like halogen (Cl, Br, I) also gave good
yields when multiple halogen substituents were present.3
Only aryl fluorides 4 that did not contain electron-
withdrawing groups or were mono-halogenated (Table 1,
entries 9–11) were unreactive.11
Table 2 Monoaryl Phloroglucinol Derivatives
Table 1 Uncatalyzed Arylation of 3,5-Dimethoxyphenol (5)
OH
OMe
OMe
1) BBr3, CH2Cl2, 0 °C
2) H2O, 0 °C
Z
Z
Y
Z
Y
Cs2CO3
NMP
6–13
+
Y
O
OH
O
OMe
F
HO
OMe
X
X
14–21
X
4
5
6–13
Entry
X
Y
Z
Product
(yield, %)
Entry
X
Y
Z
Product (yield, %)
1
2
3
4
5
6
7
8
CN
Cl
Cl
H
CF3
H
H
14 (82)
15 (97)
16 (97)
17 (97)
18 (89)a
19 (95)
20 (98)
21 (92)
1
2
CN
Cl
Cl
H
CF3
H
H
6 (99)
7 (84)
Cl
Cl
H
Cl
Cl
H
H
3
Cl
Cl
H
8 (59)
Cl
4
Cl
Br
Cl
CN
9 (60)
10 (51)a
11(62)
12 (94)
13 (94)
Br
I
Br
Cl
5
Br
I
H
6
H
H
H
CN
NO2
7
H
H
H
H
8
H
H
NO2
H
a Mixture of isomers.
NRb
NRb
NRb
9
H
Cl
H
10
11
H
H
In conclusion, an efficient, safe, and scalable method for
the preparation of phloroglucinol monoaryl ethers has
been developed. The uncatalyzed aryl coupling reaction
was chemoselective and furnished the diaryl ethers clean-
ly with few side reactions. Further manipulation of this
unique molecular scaffold toward the development of
novel cannabinoid receptor ligands will be reported else-
where.
H
H
Me
a Mixture of isomers.
b NR: no reaction, starting material recovered.
The m-chlorofluorobenzene was not at all reactive (entry
9), yet reactions of fluorobenzenes bearing dichloro sub-
stitution (entries 2–4) and dibromo substitution (entry 5)12
proceeded in good yields. Neither fluorotoluene nor fluo-
robenzene were reactive under the conditions presented
(entries 10, 11). Additionally, clear selectivity was dem-
onstrated for nucleophilic attack at the fluorine-substitut-
All chemicals were purchased from Aldrich Chemical Company
and used as received unless otherwise noted. TLC: silica gel (250
μm); visualization with UV light, I2, or phosphomolybdic acid.
1
Chromatography: silica gel 60 Å (230–400 mesh). H NMR (400
ed carbon over other halogenated sites. In all examples, MHz) and 13C NMR (100 MHz) were recorded on a Varian 400
MHz NMR spectrometer at ambient temperature in CDCl3 or
including where mixed aryl halides were employed (entry
6), the predominant product was always formed chemose-
DMSO-d6. 1H NMR chemical shifts are reported as δ values (ppm)
relative to TMS. 13C NMR chemical shifts are reported as δ values
lectively by substitution at the fluorinated carbon.
(ppm) relative to CDCl3 (77.0 ppm) or DMSO-d6 (39.5 ppm). Melt-
ing points were recorded on a Mel-temp apparatus and are uncor-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1208–1212

1210
A. M. Sherwood et al.
PAPER
rected. Atlantic Microlab, Inc., Norcross, GA performed all CHN
microanalyses.
1H NMR (CDCl3): δ = 7.37 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 2.0 Hz,
1 H), 6.88 (dd, J = 8.0, 2.0 Hz, 1 H), 6.27 (dd, J = 2.0, 2.0 Hz, 1 H),
6.17 (t, J = 2.0 Hz, 2 H), 3.76 (s, 6 H).
13C NMR (CDCl3): δ = 162.0, 158.2, 156.5, 131.2, 120.8, 118.5,
115.6, 98.0, 96.6, 55.7.
Uncatalyzed Arylation of 3,5-Dimethoxyphenol (5) to Aryl
Ethers 6–13; General Procedure A
To a solution of 3,5-dimethoxyphenol (5; 1.1 equiv) dissolved in
NMP (0.7–1.4 mL/mmol) was added Cs2CO3 (3 equiv). The mix-
ture was heated under N2 at 50 °C (oil bath) for 30 min to furnish a
dark brown phenoxide solution. The aryl fluoride 4 (1 equiv) was
syringed into the solution and the mixture was stirred at 50–110 °C
for 3–36 h. The reaction temperature was adjusted not to exceed the
boiling point of the aryl fluoride used. The reaction was monitored
by TLC (eluent: 10–30% EtOAc–hexane) until the aryl fluoride
could no longer be observed. The reaction mixture was allowed to
cool to r.t. and then added to H2O (20 mL). The resulting suspension
was extracted with toluene (3 × 15 mL). The combined organic ex-
tracts were washed with H2O (15 mL), brine (15 mL), then dried
(MgSO4), and filtered. The solvent was removed under reduced
pressure and the residue was purified by column chromatography or
triturated with H2O (10 mL), filtered, washed with H2O (10 mL),
and then dried under vacuum. Compounds isolated by trituration
were of sufficient purity to be used in subsequent reactions without
further purification (Table 1).
2,4-Dibromo-1-(3,5-dimethoxyphenoxy)benzene (10)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (1.1 g, 7.3 mmol), Cs2CO3 (3.3 g, 10 mmol), and 2,4-dibro-
mo-1-fluorobenzene12 (1.7 g, 6.7 mmol, 90% purity) in NMP (10
mL) at 65 °C for 36 h. Purification by flash chromatography (10%
EtOAc–hexane) afforded a mixture of isomers12 as a colorless oil;
yield: 1.2 g (51%).
1H NMR (CDCl3): δ = 7.76 (d, J = 2.4 Hz, 1 H), 7.37 (dd, J = 8.0,
2.4 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.24 (t, J = 2.0 Hz, 1 H), 6.12
(d, J = 2.0 Hz, 2 H), 3.74 (s, 6 H).
13C NMR (CDCl3): δ = 162.0, 158.5, 153.0, 136.2, 131.9, 122.1
117.0, 116.0, 97.0, 96.1, 55.7.
2-Chloro-1-(3,5-dimethoxyphenoxy)-4-iodobenzene (11)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (0.66 g, 4.3 mmol), Cs2CO3 (1.7 g, 5.1 mmol), and 2-chloro-
1-fluoro-4-iodobenzene (1.07 g, 4.17 mmol) in NMP (10 mL) at
65 °C for 24 h. Purification by trituration and filtration afforded a
red solid; yield: 1.0 g (62%); mp 72–74 °C.
1H NMR (CDCl3): δ = 7.77 (d, J = 2.0 Hz, 1 H), 7.50 (dd, J = 8.0,
2.0 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 6.24 (dd, J = 2.0, 2.0 Hz, 1
H), 6.13 (d, J = 2.0 Hz, 2 H), 3.74 (s, 6 H).
2-(3,5-Dimethoxyphenoxy)-6-(trifluoromethyl)benzonitrile (6)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (3.4 g, 22 mmol), Cs2CO3 (9.8 g, 30 mmol), and 2-fluoro-6-
(trifluoromethyl)benzonitrile (3.7 g, 20 mmol) in NMP (15 mL) at
65 °C for 4 h. Purification by trituration and filtration afforded a
shiny white solid; yield: 6.36 g (99%); mp 95–97 °C.
1H NMR (CDCl3): δ = 7.57 (t, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz,
1 H), 7.13 (d, J = 8.0 Hz, 1 H), 6.36 (dd, J = 2.0, 2.0 Hz, 1 H), 6.25
(t, J = 2.0 Hz, 2 H), 3.78 (s, 6 H).
13C NMR (CDCl3): δ = 162.0, 158.4, 153.7, 139.1, 137.2, 122.7,
97.0, 96.2, 55.7.
4-(3,5-Dimethoxyphenoxy)benzonitrile (12)
13C NMR (CDCl3): δ = 162.2, 161.5, 156.1, 134.4, 134.1, 123.8,
121.1, 120.4, 112.6, 100.8, 98.9, 97.9, 55.7.
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (1.1 g, 7.3 mmol), Cs2CO3 (3.3 g, 10 mmol), and 4-fluoro-
benzonitrile (0.81 g, 6.7 mmol) in NMP (10 mL) at 65 °C for 48 h.
Purification by trituration and filtration afforded a light orange sol-
id; yield: 1.6 g (94%); mp 67–68 °C.
2,4-Dichloro-1-(3,5-dimethoxyphenoxy)benzene (7)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (3.4 g, 22 mmol), Cs2CO3 (9.8 g, 30 mmol), and 2,4-dichlo-
ro-1-fluorobenzene (3.3 g, 20 mmol) in NMP (15 mL) at 120 °C for
2 h. Purification by flash chromatography (10% EtOAc–hexane) af-
forded a white solid; yield: 5.0 g (84%); mp 44–45 °C.
1H NMR (CDCl3): δ = 7.60 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz,
2 H), 6.32 (t, J = 2.0 Hz, 1 H), 6.21 (d, J = 2.0 Hz, 2 H), 3.76 (s, 6
H).
13C NMR (100 MHz, CDCl3): δ = 162.1, 161.5, 156.8, 134.8, 119.0,
118.4, 106.8, 99.0, 97.4, 55.7.
1H NMR (CDCl3): δ = 7.48 (d, J = 2.0 Hz, 1 H), 7.19 (dd, J = 8.0,
2.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.22 (dd, J = 2.0, 2.0 Hz, 1
H), 6.10 (t, J = 2.0 Hz, 2 H), 3.74 (s, 6 H).
13C NMR (CDCl3): δ = 161.9, 158.7, 151.2, 130.7, 129.7, 128.3,
127.0, 122.1, 96.7, 96.0, 55.7.
1,3-Dimethoxy-5-(4-nitrophenoxy)benzene (13)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (1.13 g, 7.3 mmol), Cs2CO3 (3.3 g, 10 mmol), and 1-fluoro-
4-nitrobenzene (0.95 g, 6.7 mmol) in NMP (10 mL) at 65 °C for 2
h. Purification by trituration and filtration afforded a light yellow
solid; yield: 1.75 g (94%); mp 116–118 °C.
1,2-Dichloro-3-(3,5-dimethoxyphenoxy)benzene (8)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (3.4 g, 22 mmol), Cs2CO3 (9.8 g, 30 mmol), and 1,2-dichlo-
ro-3-fluorobenzene (3.3 g, 20 mmol) in NMP (20 mL) at 110 °C for
20 h. Purification by flash chromatography (10% EtOAc–hexane)
afforded a shiny white solid; yield: 3.5 g (59%); mp 43–44 °C.
1H NMR (CDCl3): δ = 8.20 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 8.0 Hz,
2 H), 6.34 (t, J = 2.0 Hz, 1 H), 6.24 (d, J = 2.0 Hz, 2 H), 3.78 (s, 6
H).
13C NMR (CDCl3): δ = 163.3, 162.2, 156.7, 126.1, 117.5, 115.6,
99.6, 97.7, 55.8.
1H NMR (CDCl3): δ = 7.26 (dd, J = 8.0, 2.0 Hz, 1 H), 7.15 (t, J = 8.0
Hz, 1 H), 6.94 (dd, J = 8.0, 2.0 Hz, 1 H), 6.24 (dd, J = 2.0, 2.0 Hz,
1 H), 6.13 (d, J = 2.0 Hz, 2 H), 3.76 (s, 6 H).
13C NMR (CDCl3): δ = 162.0, 158.6, 154.9, 134.2, 127.8, 125.7,
125.2, 119.0, 97.0, 96.1, 55.7.
Demethylation of 6–13; General Procedure B
A solution of dimethoxy diaryl ether (1 equiv) was dissolved in
anhyd CH2Cl2 (5 mL/mmol) and stirred under N2 at 0 °C for 15 min.
With vigorous stirring, BBr3 (3–5 equiv) was carefully syringed
into the solution over 15 min. The ice bath was removed and the
mixture was stirred for 90 min at r.t. The reaction mixture was care-
fully transferred to an addition funnel and added dropwise to H2O
(50 mL) at 0 °C with continuous stirring over 20 min. The resulting
suspension was extracted with EtOAc (4 × 40 mL). The combined
organic extracts were washed with H2O (50 mL), brine (50 mL),
then dried (MgSO4), and filtered. The solvent was removed under
reduced pressure to afford a viscous oil. The oily residue was lyoph-
1,2-Dichloro-4-(3,5-dimethoxyphenoxy)benzene (9)
Prepared according to General Procedure A using 3,5-dimethoxy-
phenol (1.9 g, 12 mmol), Cs2CO3 (5.4 g, 17 mmol), and 1,2-dichlo-
ro-4-fluorobenzene (1.9 g, 11 mmol) in NMP (10 mL) at 120 °C for
2 h. Purification by flash chromatography (10% EtOAc–hexane) af-
forded a white solid; yield: 2.0 g (60%); mp 57–58 °C.
Synthesis 2012, 44, 1208–1212
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Phloroglucinol Monoaryl Ethers
1211
ilized under high vacuum to afford the phloroglucinol aryl ethers
14–21 as solids in pure form (Table 2).
1H NMR (DMSO-d6): δ = 9.45 (s, 2 H), 7.94 (d, J = 2.0 Hz, 1 H),
7.56 (dd, J = 8.0, 2.0 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 5.97 (t,
J = 2.0 Hz, 1 H), 5.75 (d, J = 2.0 Hz, 2 H).
2-(3,5-Dihydroxyphenoxy)-6-(trifluoromethyl)benzonitrile (14)
Prepared according to General Procedure B using a stirred solution
of 6 (4.0 g, 12 mmol) in CH2Cl2 (60 mL) at 0 °C and BBr3 (5.9 mL,
62 mmol). The resulting oily residue was purified by flash chroma-
tography (50% EtOAc–hexane) to afford a white solid; yield: 3.0 g
(82%); mp 178–180 °C.
1H NMR (DMSO-d6): δ = 9.66 (s, 2 H), 7.81 (t, J = 8.0 Hz, 1 H),
7.62 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 6.17 (s, 1 H),
6.00 (s, 2 H).
13C NMR (DMSO-d6): δ = 160.1, 158.6, 153.0, 136.1, 132.9, 123.6,
117.1, 116.3, 98.8, 96.6.
Anal. Calcd for C12H8Br2O3: C, 40.04; H, 2.24. Found: C, 39.71; H,
2.44.
5-(2-Chloro-4-iodophenoxy)benzene-1,3-diol (19)
Prepared according to General Procedure B using a stirred solution
of 11 (0.25 g, 0.64 mmol) in CH2Cl2 (3.5 mL) at 0 °C and BBr3
(0.32 mL, 3.4 mmol). The resulting oily tan residue was frozen with
liquid N2 and subjected to vacuum to afford a brown solid; yield:
0.22 g (95%); mp 75–77 °C.
13C NMR (DMSO-d6): δ = 161.5, 160.5, 156.5, 136.2, 132.7, 124.3,
122.3, 121.4, 113.2, 100.7, 100.0, 98.7.
Anal. Calcd for C14H8F3NO3: C, 56.96; H, 2.73; N, 4.74. Found: C,
56.90; H, 2.83; N, 4.54.
1H NMR (DMSO-d6): δ = 9.44 (s, 2 H), 7.90 (d, J = 2.0 Hz, 1 H),
7.66 (dd, J = 8.0, 2.0 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.98 (t,
J = 2.0 Hz, 1 H), 5.76 (d, J = 2.0 Hz, 2 H).
13C NMR (DMSO-d6): δ = 160.1, 158.5, 152.3, 138.8, 138.1, 126.8,
124.0, 98.9, 96.6, 88.7.
5-(2,4-Dichlorophenoxy)benzene-1,3-diol (15)
Prepared according to General Procedure B using a stirred solution
of 7 (0.19 g, 0.64 mmol) in CH2Cl2 (3.5 mL) at 0 °C and BBr3 (0.32
mL, 3.4 mmol). The resulting oily residue was frozen with liquid N2
and subjected to vacuum to afford a tan solid; yield: 0.17 g (97%);
mp 79–81 °C.
Anal. Calcd for C12H8ClIO3: C, 39.75; H, 2.22. Found: C, 39.50; H,
2.50.
4-(3,5-Dihydroxyphenoxy)benzonitrile (20)
1H NMR (DMSO-d6): δ = 9.45 (br s, 2 H), 7.71 (d, J = 2.0 Hz, 1 H),
7.40 (dd, J = 8.0, 2.0 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 5.98 (dd,
J = 2.0, 2.0 Hz, 1 H), 5.76 (d, J = 2.0 Hz, 2 H).
13C NMR (DMSO-d6): δ = 160.1, 158.7, 151.3, 130.7, 129.4, 129.2,
126.6, 123.5, 98.8, 96.5.
Prepared according to General Procedure B using a stirred solution
of 12 (0.70 g, 2.7 mmol) in CH2Cl2 (15 mL) at 0 °C and BBr3 (1.3
mL, 13 mmol). The resulting oily residue was frozen with liquid N2
and subjected to vacuum to afford an orange solid; yield: 0.60 g
(98%); mp 158–160 °C.
Anal. Calcd for C12H8Cl2O3: C, 53.17; H, 2.97. Found: C, 53.21; H,
2.80.
1H NMR (DMSO-d6): δ = 9.57 (br s, 2 H), 7.79 (d, J = 8.0 Hz, 2 H),
7.08 (d, J = 8.0 Hz, 2 H), 6.10 (dd, J = 2.0, 2.0 Hz, 1 H), 5.92 (d,
J = 2.0 Hz, 2 H).
13C NMR (DMSO-d6): δ = 161.6, 160.3, 156.8, 135.2, 119.4, 118.3,
105.6, 100.1, 98.9.
5-(2,3-Dichlorophenoxy)benzene-1,3-diol (16)
Prepared according to General Procedure B using a stirred solution
of 8 (0.19 g, 0.64 mmol) in CH2Cl2 (3.5 mL) at 0 °C and BBr3 (0.32
mL, 3.4 mmol). The resulting oily residue was frozen with liquid N2
and subjected to vacuum to afford an off-white solid; yield: 0.17 g
(97%); mp 104–106 °C.
Anal. Calcd for C12H8Cl2O3: C, 68.67; H, 3.99; N, 6.16. Found: C,
68.51; H, 4.11; N, 6.02.
5-(4-Nitrophenoxy)benzene-1,3-diol (21)
1H NMR (DMSO-d6): δ = 9.46 (s, 2 H), 7.45 (dd, J = 8.0, 2.0 Hz, 1
H), 7.36 (t, J = 8.0 Hz, 1 H), 7.08 (dd, J = 8.0, 2.2 Hz, 1 H), 5.98
(dd, J = 2.0, 2.0 Hz, 1 H), 5.77 (d, J = 2.0 Hz, 2 H).
13C NMR (DMSO-d6): δ = 160.2, 158.5, 153.8, 133.4, 129.6, 126.4,
124.4, 120.5, 99.0, 96.6.
Prepared according to General Procedure B using a stirred solution
of 13 (2.0 g, 7.7 mmol) in CH2Cl2 (30 mL) at 0 °C and BBr3 (2.5
mL, 27 mmol) according to General Procedure B. The resulting oily
residue was frozen with liquid N2 and subjected to vacuum to afford
a light yellow solid; 1.6 g (89%); mp 127–129 °C.
Anal. Calcd for C12H8Cl2O3: C, 53.17; H, 2.97. Found: C, 53.01; H,
3.00.
1H NMR (DMSO-d6): δ = 9.62 (br s, 2 H), 8.22 (d, J = 8.0 Hz, 2 H),
7.11 (d, J = 8.0 Hz, 2 H), 6.12 (br s, 1 H), 5.94 (br s, 2 H).
13C NMR (DMSO-d6): δ = 163.5, 160.4, 156.6, 142.8, 126.7, 118.1,
100.4, 99.2.
5-(3,4-Dichlorophenoxy)benzene-1,3-diol (17)
Prepared according to General Procedure B using a stirred solution
of 9 (0.19 g, 0.64 mmol) in CH2Cl2 (3.5 mL) at 0 °C and BBr3 (0.32
mL, 3.4 mmol). The resulting oily residue was frozen with liquid N2
and subjected to vacuum to afford an off-white solid; yield: 0.16 g
(92%); mp 91–92 °C.
Anal. Calcd for C12H8Cl2O3: C, 58.30; H, 3.67; N, 5.67. Found: C,
58.81; H, 3.99; N, 5.29.
Acknowledgment
1H NMR (DMSO-d6): δ = 9.49 (br s, 2 H), 7.59 (dd, J = 8.0, 2.0 Hz,
1 H), 7.26 (d, J = 2.0 Hz, 1 H), 6.99 (dd, J = 8.0, 2.0 Hz, 1 H), 6.02
(br s, 1 H), 5.85 (d, J = 2.0 Hz, 2 H).
This research was funded by the National Institute on Drug Abuse
(DA023916) and the University of New Orleans.
13C NMR (DMSO-d6): δ = 160.2, 158.0, 156.9, 132.5, 132.1, 125.9,
121.0, 119.6, 99.5, 98.0.
References
Anal. Calcd for C12H8Cl2O3: C, 53.17; H, 2.97. Found: C, 53.17; H,
3.17.
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© Georg Thieme Verlag Stuttgart · New York