A highly efficient copper-catalyzed method for the synthesis of 2-hydroxybenzamides in water

Article abstract of DOI:10.1055/s-0031-1289755

An efficient copper-catalyzed synthetic method for the preparation of 2-hydroxybenzamides is described for the first time from 2-chlorobenzamide substrates using copper iodide/1,10-phenanthroline and a base, potassium hydroxide, in neat water. By using this reaction, a series of 2-hydroxybenzamides with functional groups such as fluoro, chloro, iodo, methoxy, amide, and alcohol have been obtained in 33-96% yield. Other aromatic 2-chloroarylamides such as naphthalene, pyridine, and thiophene are found to be equally compatible to the reaction. It is proposed that the reaction proceed via formation of copper-amide complex, which may facilitate the hydroxylation in water. Overall, the first report on copper-catalyzed hydroxylation reaction in water and first catalytic route for the synthesis of 2-hydroxybenzamides is presented. Simple purification procedure and convenience of employing low-cost reagents in neat water make this method practical and economical for the synthesis of 2-hydroxybenzamides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289755

PAPER
▌1417
paper
A Highly Efficient Copper-Catalyzed Method for the Synthesis of 2-Hydroxy-
benzamides in Water
Copper-Catalyzed Hydroxylation in Aqueous Medium
Shah Jaimin Balkrishna, Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research (IISER), Bhopal 462023, MP, India
Fax +91(755)409 2392; E-mail: SangitKumar@iiserbhopal.ac.in
Received: 19.12.2011; Accepted after revision: 19.03.2012
of aryl halides has attracted considerable interest in recent
Abstract: An efficient copper-catalyzed synthetic method for the
time.8–11 The pioneering work of Taillefer et al.8 and You
preparation of 2-hydroxybenzamides is described for the first time
et al.9a on copper-catalyzed hydroxylation reaction led to
study this reaction for the synthesis of useful organic mol-
from 2-chlorobenzamide substrates using copper iodide/1,10-phen-
anthroline and a base, potassium hydroxide, in neat water. By using
this reaction, a series of 2-hydroxybenzamides with functional ecules and also to search improvised reaction conditions.
groups such as fluoro, chloro, iodo, methoxy, amide, and alcohol
have been obtained in 33–96% yield. Other aromatic 2-chloroaryl-
Water compatible ligands, 8-hydroxyquinolin-N-oxide
and lithium pipecolinate have been utilized to exploit var-
amides such as naphthalene, pyridine, and thiophene are found to be
ious aryl halides in copper-catalyzed hydroxylation reac-
equally compatible to the reaction. It is proposed that the reaction
tion.9b,g Similarly, D-glucose is employed as a green
proceed via formation of copper-amide complex, which may facili-
ligand by Sekar et al. to further improvise the copper-cat-
alyzed hydroxylation reaction conditions.9f Arylboronic
acid substrates have been utilized for copper-catalyzed
hydroxylation reaction in neat water at room tempera-
ture.9e,h Although the reaction shows broad functional
group tolerance under normal reaction conditions, arylbo-
ronic acid substrates are required for hydroxylation reac-
tion. Recently, phase-transfer reagent such as
tetrabutylammonium hydroxide or tetrabutylammonium
bromide has been employed to carry out copper-catalyzed
hydroxylation reaction in neat water on aryl halide sub-
strates.9c,10 It is now well established that neat water as a
solvent is not effective for copper-catalyzed hydroxyl-
ation reaction of aryl halides, unless phase-transfer cata-
lyst or organic solvent is employed. In this context,
development of a copper-catalyzed hydroxylation reac-
tion in neat water using simple reagents would not only be
cost effective, environmentally benign but also expected
with greater chemoselectivity.12,13
tate the hydroxylation in water. Overall, the first report on copper-
catalyzed hydroxylation reaction in water and first catalytic route
for the synthesis of 2-hydroxybenzamides is presented. Simple pu-
rification procedure and convenience of employing low-cost re-
agents in neat water make this method practical and economical for
the synthesis of 2-hydroxybenzamides.
Key words: copper, 2-hydroxybenzamides, hydroxylation, cataly-
sis in water, C–O coupling
2-Hydroxybenzamides have numerous applications such
as anion binding, sensors, as well as a ligand for various
metal complex formations.1 Also, 2-hydroxybenzamides
have been used as precursors for the synthesis of other li-
gands such as 2-(2′-hydroxyphenyl)-2-oxazoline.2 Fur-
thermore, a wide range of pharmacological activities
namely antibacterial, antifungal, and anti-inflammatory
have been well documented.3 Recently, 2-hydroxybenz-
amides have also attracted considerable interest due to
their cancer, psoriasis, and restenosis related activities.4
To the best of our knowledge, copper-catalyzed hydroxyl-
ation reaction of aryl halides in neat water has not been de-
scribed till today. Also, copper-catalyzed hydroxylation
of 2-halobenzamides has not been reported in the litera-
ture. Here in this study, for the first time, we report an ef-
ficient and practical copper-catalyzed hydroxylation
reaction for the synthesis of 2-hydoxybenzamides in neat
water.
Present methods for the synthesis of 2-hydroxybenz-
amides depend on salicylic acid, which is obtained by the
reaction of sodium phenolate with carbon dioxide at high
pressure (100 atm) and high temperature (390 K) on com-
mercial scale, a process known as Kolbe–Schmitt reac-
tion. Moreover, synthesis of some of the substituted
salicylic acids requires multiple steps.5 Therefore, it
would be worth developing an economical and environ-
mentally benign method for the synthesis of 2-hydroxy-
benzamides from readily available and economical
substrates under mild reaction conditions. Copper-cata-
lyzed carbon–heteroatom (N, O, S, and Se) coupling reac-
tions have emerged as a new strategy for the synthesis of
heteroatom containing organic molecules.6–11 Among
these coupling reactions, copper-catalyzed hydroxylation
Recently, our group has developed a copper-catalyzed
carbon–selenium–nitrogen bond-forming reaction from
2-halobenzamides and selenium powder in an organic sol-
vent, DMF.14 When the same reaction was performed in
water, the reaction does not proceed to form Se–N hetero-
cycles, however, the reaction afforded 2-hydroxybenz-
amide in excellent yield (96%) in 15 minutes (Scheme 1).
The excellent yield of 2-hydroxybenzamide 1 under be-
nign reaction conditions in neat water encouraged us to
develop a simple reaction protocol for the synthesis of 2-
hydroxybenzamide from 2-chlorobenzoyl chloride in one
SYNTHESIS 2012, 44, 1417–1426
Advanced online publication: 12.04.2012
DOI: 10.1055/s-0031-1289755; Art ID: SS-2011-N1148-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1418
S. J. Balkrishna, S. Kumar
PAPER
were screened to achieve complete conversion of 2-chlo-
ro-N-benzylbenzamide into 2-hydroxybenzamide. Weak
bases such as potassium and sodium carbonate were not
effective for the complete conversion of 2-chlorobenz-
amide (Table 1, entries 1 and 2). Strong bases such as
KOH and NaOH were found to be effective for the com-
plete conversion of the substrate.
O
O
I
N
Se
Bn
Bn
Bn
CuI, 1,10-
N
phenanthroline
H
O
Se powder
K2CO3, H2O
Δ, 100 °C
N
H
OH
We chose KOH for further optimization of reaction con-
ditions. In the next set of experiments, the concentration
of KOH was varied in the presence of 10 mol% of CuI/L
and product formation was observed for 10 hours (Figure
1).
96 %
Scheme 1 Copper-catalyzed synthesis of 2-hydroxybenzamide from
2-iodobenzamide. Isolated yield. Monitored by TLC and con-
firmed by NMR and mass spectrometry.
a
b
pot. The practical advantages of choosing 2-chloroaroyl
chloride/2-chlorobenzamide as substrates are as follows:
a) although, reaction time is generally longer for chloro
substrates than the corresponding bromo and iodo sub-
strates, the chloro substrates are very cheap; b) a diversely
substituted 2-chlorobenzoyl chloride with methoxy, chlo-
ro, fluoro, nitro, etc. groups and most importantly 2-chlo-
roaroyl chloride for naphthalene, pyridine, and thiophene
are readily available, which could be valuable for the syn-
thesis of a diverse series of 2-hydroxyarylamide under one
set of reaction conditions. We chose 2-chloro-N-benzyl-
benzamide substrate (prepared in situ from 2-chloroben-
zoyl chloride and benzylamine) to optimize the reaction
conditions in neat water (Table 1). Initially, various bases
Figure 1 Effect of KOH on the CuI-catalyzed hydroxylation reac-
tion. X-axis represents four set of experiments: 1 (1 equiv of KOH),
2 (3 equiv of KOH), 3 (5 equiv of KOH), and 4.0 (8 equiv of KOH)
and Y-axis represents percentage conversion of substrate. Reaction
was carried out on a 1 mmol scale, progress of reaction was monitored
for 10 h, and each experiment was repeated twice.
Table 1 Optimization of Reaction Conditions for 2-Chlorobenzoyl
Chloride
O
O
Bn
It is apparent from Figure 1 that eight equivalents of KOH
is necessary for the complete conversion of substrate in 10
hours. Further increase in KOH did not produce any effect
on reaction time. Excess of KOH (8–12 equiv) and pro-
longed heating did not lead to any side product and also
yield of hydroxylated product remained nearly the same.
It is worth noting that the yield of 1 obtained from 2-chlo-
ro-N-benzylbenzamide is the same as obtained from the
corresponding 2-iodo-N-benzylbenzamide substrate in
our reaction system (96% yield of 1 from chloro and iodo
substrates). Next, catalyst loading versus reaction time is
studied using three concentration sets of CuI and ligand
(10, 15, and 25 mol%) using eight equivalents of KOH at
100 °C. When catalyst concentration was lowered from
25 to 10 mol%, considerable increase in reaction time was
observed. Since product obtained under reaction condi-
tions using 10 mol% of CuI/L and eight equivalents of
base require only minimum purification (for purity of
crude product 1, see: 1H and 13C NMR in the Supporting
Information, Figure S1 and S2), 10 mol% CuI and 1,10-
phenanthroline was used for further investigation. Having
optimized conditions in hand, diversely substituted 2-hy-
droxybenzamides 1–22 were synthesized from 2-chloro
substrates (Tables 2–4).
Cl
1. BnNH2, CH2Cl2
N
H
2. CuI (10 mol%)
1,10-phenanthroline
KOH, H2O, Δ, 100 °C
Cl
OH
Entry
CuI/L
(mol%) (equiv)
Base
Time
(h)
Conversion Yield
(%)a
(%)b
1
2
10
10
10
10
10
10
10
15
25
25e
K2CO3 (10)
14
14
10
10
10
10
10
7
86
74
80
66c
95
96
ndd
nd
64
94
97
nd
Na2CO3 (10)
NaOH (8)
KOH (8)
KOH (1)
KOH (3)
KOH (5)
KOH (8)
KOH (8)
KOH (8)
3
100
100
30
4
5
6
40
7
70
8
100
100
10
9
1
10
14
a Based on substrate recovered from the reaction mixture.
b Isolated yield.
c Formation of side product was also observed as monitored by TLC.
d nd = not determined.
2-Chlorobenzamide substrates were prepared from the re-
spective benzoyl chlorides and primary amines in dichlo-
romethane. The resulting crude 2-chlorobenzamides were
e No ligand was used.
Synthesis 2012, 44, 1417–1426
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Hydroxylation in Aqueous Medium
1419
subjected to copper-catalyzed hydroxylation without fur- h) considerably (Table 2, entry 3). By following the cop-
ther purification (for details, please see experimental pro- per-catalyzed hydroxylation protocol, nitro-substituted 2-
cedure). Next, fluorinated 2-hydroxybenzamides 3–5 hydroxybenzamides 6 and 7 were also obtained in 85 and
were obtained in 72–87% yield from readily accessible 2- 87% yield, respectively. Electron-rich methoxy-substitut-
chlorobenzoyl chloride substrates in one pot (Table 2, en- ed 2-chlorobenzamide substrates underwent hydroxyl-
tries 3–5). 4-Fluoro and 2-chloro-3,4-difluorobenzamides ation reaction successfully (Table 2, entries 8 and 9).
reacted completely to give respective 2-hydroxybenz- However, 3-methoxy-substituted 2-hydroxybenzamide 9
amides 4 and 5 in 8 and 10 hours, respectively; however, was obtained in 44% yield, and 40% of unreacted sub-
substitution at 5-position increases the reaction time (16 strate was recovered.
Table 2 Copper-Catalyzed Synthesis of Substituted 2-Hydroxybenzamides by Hydroxylation of in situ Prepared 2-Chlorobenzamides in
Water at 100 °Ca
Yield (%)b
Entry
Substrate
Product
O
O
R
R
N
H
N
H
OH
Cl
1
2
R = Bn
R = Ph
R = Bn
R = Ph
1
2
96
94
O
O
6
6
Bn
Bn
1
2
1
2
5
F
5
F
N
N
H
H
4
3
4
3
Cl
OH
3
4
5
5-F
4-F
5-F
4-F
3
4
5
72
83
87
4,5-difluoro
4,5-difluoro
O
O
O2N
Bn
O2N
Bn
N
H
N
H
6
7
8
6
7
8
85
87
61
Cl
OH
Bn
O
O
Bn
N
N
H
H
Cl
OH
NO2
NO2
O
O
MeO
Bn
MeO
Bn
N
H
N
H
Cl
R
OH
O
O
N
H
R
N
H
9
9
44
64
Cl
OH
O
OMe
OMe
R = 1-(naphthalen-1-yl)ethyl
O
OH
OH
N
H
N
H
10
10
OH
Cl
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1417–1426

1420
S. J. Balkrishna, S. Kumar
PAPER
Table 2 Copper-Catalyzed Synthesis of Substituted 2-Hydroxybenzamides by Hydroxylation of in situ Prepared 2-Chlorobenzamides in
Water at 100 °Ca (continued)
Yield (%)b
91
Entry
11
Substrate
Product
O
O
Bn
Bn
N
N
11
12
H
H
Cl
Cl
Cl
OH
O
O
Bn
Bn
12
90
N
N
H
H
Cl
OH
Bn
O
O
Bn
N
N
13
14
15
13
14
15
62
33
57
H
H
N
Cl
N
O
OH
O
Bn
Bn
N
H
N
H
OH
Cl
S
S
Cl
OH
H
H
N
N
Bn
Bn
S
S
O
O
a Reaction conditions: 1. 2-chlorobenzoyl chloride (1.0 equiv), primary amine (1.5 equiv), CH2Cl2 (solvent), 0 °C to r.t., 3–6 h; 2. CuI (10
mol%), 1,10-phenanthroline (10 mol%), KOH (8.0 equiv), H2O (solvent), 100 °C, unless otherwise stated.
b Isolated yield.
Next, the generality of hydroxylation reaction on 2-chlo- Similarly, when the copper-catalyzed reaction was per-
ro-N-(2-hydroxyethyl)benzamide having an additional formed on 2-chloro-, 2-bromo-, and 2-iodo-N-(2-iodophe-
acidic proton was studied (Table 2, entry 10; for more nyl)benzamides (Scheme 2), hydroxylation occurred
substrates with an additional acidic proton, see Table 3). chemoselectively at 2-position and iodine substituent re-
2-Hydroxy-N-(2-hydroxyethyl)benzamide (10), a precur- mained unaffected. From this study, it is observed that hy-
sor for the synthesis of naturally occurring 2-(2′-hydroxy- droxylation occurred selectively at ortho position (ortho
phenyl)-2-oxazoline ligand,2 was obtained in 84% yield in to benzamide functionality) and other halogen (chlorine
one pot from 2-chlorobenzoyl chloride.
and iodine) substituent remains unaffected under the reac-
tion conditions. This excellent selectivity could be due to
anchimeric effect of ortho amide functionality.
After studying amenability of copper-catalyzed hydroxyl-
ation reaction to the substrates containing additional acid-
ic proton, our attention turned to chlorine, bromine, and Other aromatics such as naphthyl, pyridyl, and thiophenyl
iodine substituted substrates (Table 2, entry 11, and also showed compatibility in copper-catalyzed hydroxyl-
Scheme 2). N-Benzyl-2,4-dichlorobenzamide having an ation reaction and the yield of the reaction seems invari-
additional chloro substituent at the 3-position reacted che- able with respect to heteroaryl amides. 3-Hydroxy-2-
moselectively to give 4-chloro-2-hydroxybenzamide 11 naphthamide has been proven to be effective precursor for
in 91% yield.
the sterioselective synthesis of 1,10-bi-2-naphthol
O
O
O
CuI, 1,10-
N
N
N
phenanthroline
H
H
H
+
I
OH
I
X
KOH, H2O
Δ, 100 °C
OH
OH
X = Cl, Br, I
16 (92% from iodo)a
16 (89% from bromo)a none
16 (86% from chloro)a traceb
none
Scheme 2 Chemoselective copper-catalyzed hydroxylation. a Isolated yield. b Monitored by TLC and confirmed by NMR and mass spectro-
metry.
Synthesis 2012, 44, 1417–1426
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Hydroxylation in Aqueous Medium
1421
(BINOL), which is a well-known chiral ligand.15 Here, 3-
Table 4 Copper-Catalyzed Synthesis of Bis(2-hydroxybenzamide)
hydroxy-2-naphthamide 12 was obtained in 90% yield Compounds in Watera
from 3-chloronaphthoyl chloride in one pot using copper-
catalyzed hydroxylation reaction in neat water.
O
O
O
Cl
1. diamine, CH2Cl2
N
N
Synthesis of 2-hydroxynicotinamides has not been well
explored16 compared to 2-hydroxybenzamides presum-
ably due to sluggish reaction between 2-hydroxynicotino-
yl chloride and primary amine. 2-Hydroxynicotinamide
13 was readily obtained from easily available 2-chloronic-
otinic acid in 62% yield in one pot. Similar to pyridine,
synthesis of thiophene-based hydroxy amide is also not
well documented because of scarce availability of 3-hy-
droxythiophene-2-carboxylic acid. Moreover, synthesis
of 2-hydroxythiophenamide and its related substrate 2-hy-
droxythiophene-3-carboxylic acid has not been described
in the literature. Copper-catalyzed reaction in neat water
can be exploited not only for the synthesis of 3-hydroxy-
thiophenamide 15 but also for the synthesis of new 2-hy-
droxythiophenamide 14.
H
H
2. CuI, 1,10-phenanthroline
Cl
OH
HO
KOH, H2O, Δ, 100 o
C
Entry Product
Yield
(%)b
O
O
1
19 77
N
H
N
H
OH
O
HO
O
N
H
N
H
2
20 72
OH
O
HO
O
The generality of copper-catalyzed hydroxylation reac-
tion of 2-bromo-N1,N3- diphenylethylisophthalamide sub-
strates having an additional amide functionality was also
studied (Table 3). 2-Bromoisophthaloyl dichloride, which
was readily available to us, was used for amidation fol-
lowed by copper-catalyzed hydroxylation reaction. 2-Hy-
droxy-bis-benzamides 17 and 18 were obtained for the
first time in 84 and 80% yield using copper-catalyzed re-
action in neat water.
N
H
N
H
3
21 63
OH
O
HO
NO2
NO2
O
4
22 74
N
H
N
H
OH
HO
a Reaction conditions: 1. 2-chlorobenzoyl chloride (1.0 equiv), prima-
ry amine (0.5 equiv), CH2Cl2 (solvent), 0 °C to r.t., 6 h; 2. CuI/1,10-
phenanthroline (20 mol%), KOH (8.0 equiv), H2O (solvent), 100 °C.
b Isolated yield.
Table 3 Copper-Catalyzed Synthesis of 2-Hydroxy-N1,N3-diphenyl-
ethylisophthalamides in Watera
R
O
R
O
Cl
Br
Cl
NH OH HN
1. RNH2, CH2Cl2
O
O
gave bis-hydroxybenzamides in one pot (Table 4, entries
1–4).
2. CuI, 1,10-phenanthroline
KOH, H2O, Δ, 100 °C
The plausible catalytic cycle is presented in Scheme 3 for
the copper-catalyzed hydroxylation of 2-chlorobenz-
amides under basic conditions in neat water. Copper(I)
may react with the amide in the presence of a base and
forms LCu(I)amide complex A. After this, oxidative addi-
tion of Cu into the C–Cl bond would lead to the formation
of a Cu(III) intermediate B, which may undergo substitu-
tion reaction with OH– leading hydroxocopper intermedi-
ate C. Reductive elimination would produce 2-
hydroxybenzamide and concomitant release of LCu(I)
complex. Although, other copper complex species may be
present in the reaction mixture, concentration of
LCu(I)amide A would be much higher as reported earli-
er.18 Furthermore, oxidative addition of aryl chloride to
LCu(I)amide is expected to be more favorable due to in-
tramolecular nature of reaction.
Yield (%)b
84
Entry
1
R
17
OMe
OMe
2
18
80
a Reaction conditions: 1. 2-bromoisophthaloyl dichloride (1.0 equiv),
primary amine (2.4 equiv), CH2Cl2 (solvent), 0 °C to r.t., 5 h; 2.
CuI/1,10-phenanthroline (10 mol%), KOH (8.0 equiv), H2O (sol-
vent), 100 °C.
b Isolated yield.
After studying the synthesis of 2-hydroxybenzamides, we
explored the synthesis of bis(2-hydroxybenzamide) com-
pounds (Table 4), which have been used as a ligand for
metal complexation reaction.17
2-Chloro-N,N-diethylbenzamide substrate lacking acidic
proton was subjected to hydroxylation reaction under
identical reaction conditions to gain further insight into
the mechanism. Interestingly, formation of hydroxylated
product was not observed as monitored by TLC and mass
spectrometry. Similarly simple iodo- and chlorobenzene
For this purpose, 2-chlorobenzoyl chloride was treated
with diamines such as ethylenediamine, propylenedi-
amine, and 1,2-diaminocyclohexane. Copper-catalyzed
hydroxylation reaction on resulted diamide substrates
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1417–1426

1422
S. J. Balkrishna, S. Kumar
PAPER
ica gel plates. Substituted benzoyl chlorides were prepared from
respective benzoic acids by refluxing with excess SOCl2. Excess of
SOCl2 was removed under vacuo and the resulting residue was used
for amide preparation without further purification.
O
O
O
NHR
KOH
NR
NR
CuL
Cl
CuL
Cl
Cl
B
A
N-Benzyl-2-hydroxybenzamide (1); Typical Procedure
In a 50 mL capacity single-necked round-bottomed flask, 2-chloro-
benzoyl chloride (0.425 g, 2.4 mmol) was dissolved in anhyd
CH2Cl2 (15 mL) and cooled to 0 °C. To this cold solution was slow-
ly added benzylamine (0.385 g, 3.6 mmol) in CH2Cl2 (10 mL) from
a dropping funnel. The resulting reaction mixture was stirred for 1
h at 0 °C and 2 h at r.t. Then, CH2Cl2 was evaporated under reduced
pressure at 40 °C. The residue was washed with H2O (15 mL) and
the aqueous layer was decanted. To the crude 2-chloro-N-benzyl-
benzamide were added H2O (8 mL), CuI (46 mg, 0.24 mmol), and
1,10-phenanthroline (44 mg, 0.24 mmol), and the mixture was
stirred at r.t. for 10 min. Then, KOH (1.4 g, 24.4 mmol) was added.
After this, the reaction flask was fitted with a reflux condenser and
the mixture was heated at reflux in an oil bath at 100 °C for 10 h.
Progress of the reaction was monitored by TLC (eluent: hexane–
EtOAc, 8:2). The reaction mixture was acidified with 10% aq HCl
Cu+
L
– OH
Cl–
O
O
O
NR
NR
NHR
CuL
CuL
HO
OH
OH
H2O
D
C
Scheme 3 Proposed reaction mechanism for copper-catalyzed hy-
droxylation of 2-chlorobenzamide
failed to yield phenol under our reaction conditions in neat
water. Chlorobenzene was recovered 90% from the reac- and extracted with EtOAc (3 × 30 mL). The combined EtOAc lay-
ers were dried (Na2SO4) and evaporated under reduced pressure at
40 °C. The crude product was of almost pure quality (see NMR data
in Supporting Information for crude product) and was purified by
tion mixture after heating for 24 hours and iodobenzene
was converted into a side product. 2-Chlorobenzoic acid
substrate having CO2H coordinating group also failed to
give 2-hydroxybenzoic acid under our reaction conditions
on heating for 48 hours.19 It is worth citing that copper-
catalyzed hydroxylation in 2-chlorobenzoic acid, similar
substrate to 2-chlorobenzamide, has been studied. How-
column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.53 g (96%); colorless crystals; mp 134–136 °C (Lit.20 mp 134–
137 °C).
1H NMR (400 MHz, CDCl3): δ = 12.34 (s, 1 H), 7.44–7.36 (m, 7 H),
7.02 (dd, J = 8.4, 1.0 Hz, 1 H), 6.85 (m, 1 H), 6.65 (s, 1 H), 4.66 (d,
ever, the reaction requires longer time and phase-transfer J = 5.7 Hz, 2 H).
reagent to achieve 2-hydroxybenzoic acid in 66% yield.9c
These control experiments and related reported study sug-
gest that the presence of amidic proton (NH) in the sub-
strate is crucial for hydroxylation in neat water.
13C NMR (100 MHz, CDCl3): δ = 169.8, 161.6, 137.4, 134.4, 128.9,
127.92, 127.91, 125.4, 118.70, 118.69, 114.1, 43.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H14NO2: 226.0862; found:
226.0869.
In summary, we have developed a simple and efficient
copper-catalyzed method for the synthesis of substituted
2-hydroxybenzamides from 2-chloroaroyl chloride in one
pot. The reaction system requires readily available sub-
strates and reagents such as 2-chloroaroyl chlorides, pri-
mary amines, copper iodide, 1,10-phenanthroline,
potassium hydroxide, and eco-friendly solvent water. Fur-
thermore, mild reaction conditions and simple purifica-
tion procedure make this method highly practical. We
have also achieved the synthesis of some important 2-hy-
droxybenzamides, which are not accessible by other
methods. Overall, broader substrate scope, excellent se-
lectivity, and mild reaction conditions will be useful for
the synthesis of substituted 2-hydroxybenzamides on
smaller to larger scale. Further investigation to broaden
the substrate scope of this copper-catalyzed hydroxylation
reaction in neat water is currently ongoing in our labora-
tory.
2-Hydroxy-N-phenylbenzamide (2)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.60 g (94%); colorless crystals; mp 129 °C (Lit.21 mp 129–131 °C).
1H NMR (400 MHz, CDCl3): δ = 12.0 (s, 1 H), 8.0 (s, 1 H), 7.62–
7.54 (m, 3 H), 7.49–7.38 (m, 3 H), 7.23 (m, 1 H), 7.05 (dd, J = 8.4,
1.0 Hz, 1 H), 6.94 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 168.4, 161.8, 136.6, 134.7, 129.2,
125.5, 125.4, 121.3, 119.0, 118.9, 114.6.
HRMS (ESI): m/z [M + H]+ calcd for C13H12NO2: 212.0706; found:
212.0702.
N-Benzyl-5-fluoro-2-hydroxybenzamide (3)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.20 g (72%); colorless crystals; mp 150–152 °C.
IR (KBr): 3365, 3055, 2930, 1643, 1601, 1555, 1505, 1455, 1420,
1367, 1265, 1236, 1164, 1142, 1106, 739, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 12.0 (s, 1 H), 7.42–7.34 (m, 6 H),
7.15 (m, 1 H), 7.06 (dd, J = 8.8, 3.0 Hz, 1 H), 7.0 (m, 1 H), 6.5 (br
s, 1 H), 4.64 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 169.2, 167.5, 164.9, 163.9, 163.8,
137.2, 129.0, 128.0, 127.9, 127.3, 127.2, 110.82, 110.79, 106.7,
106.5, 105.4, 105.2, 43.7.
All NMR experiments were carried out on 400 or 500 MHz spec-
trometers in DMSO-d6 or CDCl3 and NMR chemical shifts are re-
ported in ppm referenced to the solvent peaks of CDCl3 [7.26 ppm
for 1H and 77.1 (± 0.1) ppm for 13C, respectively] or DMSO-d6 (2.50
HRMS (ESI): m/z [M + Na]+ calcd for C14H12FNO2 + Na: 268.0744;
found: 268.0741.
1
ppm for H and 39.5 ppm for 13C, respectively). Mass analysis is
N-Benzyl-4-fluoro-2-hydroxybenzamide (4)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.155 g (83%); colorless crystals; mp 86 °C.
performed on quadruple-time of flight (Q-TOF) mass spectrometer
equipped with an ESI source (+ve or –ve). Melting points are uncor-
rected. CuI and 1,10-phenanthroline were used as received from
Aldrich. Silica gel (60 mesh size) was used for column chromato-
graphy. TLC analysis of reaction mixtures was performed using sil-
IR (KBr): 3359, 2923, 1647, 1605, 1551, 1501, 1355, 1238, 831
cm–1.
Synthesis 2012, 44, 1417–1426
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Hydroxylation in Aqueous Medium
1423
1H NMR (400 MHz, CDCl3): δ = 12.0 (s, 1 H), 7.43–7.32 (m, 5 H),
7.18–7.13 (m, 1 H), 7.06 (dd, J = 8.8, 3.0 Hz, 1 H), 7.0–6.97 (m, 1
H), 6.53 (s, 1 H), 4.65 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 168.91, 168.88, 157.76, 157.74,
156.1, 153.7, 137.1, 128.9, 128.0, 127.9, 121.5, 119.9, 119.8,
113.96, 113.90, 111.2, 110.9, 43.9.
1H NMR (400 MHz, CDCl3): δ = 11.90 (s, 1 H), 8.14 (d, J = 8.3 Hz,
1 H), 7.90 (dd, J = 7.9, 1.7 Hz, 1 H), 7.85 (d, J = 8.2 Hz, 1 H), 7.62–
7.49 (m, 4 H), 7.02 (dd, J = 8.2, 1.3 Hz, 1 H), 6.96 (dd, J = 8.1, 1.2
Hz, 1 H), 6.85 (br d, J = 7.5 Hz, 1 H), 6.75 (t, J = 8.0 Hz, 1 H), 6.12
(quint, J = 7.0 Hz, 1 H), 3.90 (s, 3 H), 1.80 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.4, 151.1, 148.9, 137.7, 134.0,
131.0, 128.9, 128.6, 126.8, 126.0, 125.2, 123.1, 122.7, 118.2, 117.6,
114.8, 114.7, 56.1, 45.2, 20.8.
HRMS (ESI): m/z [M + Na]+ calcd for C14H12FNO2 + Na: 268.0744;
found: 268.0786.
HRMS (ESI): m/z [M + Na]+ calcd for C20H19NO3 + Na: 344.1257;
found: 344.1260.
N-Benzyl-4,5-difluoro-2-hydroxybenzamide (5)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.24 g (87%); colorless crystals; mp 118 °C.
2-Hydroxy-N-(2-hydroxyethyl)benzamide (10)
Column chromatography [silica gel, EtOAc–hexane (2:3)]; yield:
0.23 g (64%); colorless crystals; mp 113–114 °C (Lit.24 mp 113–
114 °C).
1H NMR (400 MHz, CDCl3): δ = 12.2 (s, 1 H), 7.46 (dd, J = 8.0, 1.2
Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.81 (t,
J = 7.6 Hz, 1 H), 3.80 (t, J = 5.0 Hz, 2 H), 3.57 (q, J = 5.3 Hz, 2 H),
3.07 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.6, 160.9, 134.3, 126.0, 119.0,
118.3, 114.3, 42.1, 29.7.
HRMS (ESI): m/z [M – H]+ calcd for C9H10NO3: 180.0655; found:
180.0708.
IR (KBr): 3374, 2921, 1598, 1558, 1515, 1371, 1270, 1199, 1156,
860, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 12.4 (s, 1 H), 7.43–7.35 (m, 5 H),
7. 19 (t, J = 9.4 Hz, 1 H), 6.81 (m, 1 H), 6.44 (s, 1 H), 4.64 (d, J =
5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 168.5, 159.1, 159.0, 155.3, 155.2,
152.8, 152.6, 144.6, 144.5, 142.2, 142.1, 137.0, 129.011, 128.1,
128.0, 113.33, 113.3, 113.14, 113.12, 109.5, 107.3, 107.1, 43.9.
HRMS (ESI): m/z [M + Na]+ calcd for C14H11F2NO2 + Na:
286.0648; found: 286.0650.
N-Benzyl-2-hydroxy-5-nitrobenzamide (6)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.24 g (85%); yellow crystals; mp 221–223 °C (Lit.22 mp 221–
223 °C).
1H NMR (400 MHz, CDCl3): δ = 12.3 (s, 1 H), 8.51 (dd, J = 7.8, 1.8
Hz, 1 H), 8.27 (dd, J = 8.4, 1.7 Hz, 1 H), 8.11 (br s, 1 H), 7.40–7.33
(m, 5 H), 7.12 (t, J = 7.8 Hz, 1 H), 4.71 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 162.6, 152.4, 138.4, 136.7, 133.7,
127.69, 127.66, 126.6, 126.5, 121.6, 118.8, 43.0.
HRMS (ESI): m/z [M + Na]+ calcd for C14H12FNO2 + Na: 268.0744;
found: 268.0786.
N-Benzyl-4-chloro-2-hydroxybenzamide (11)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.29 g (91%); colorless crystals; mp 124 °C (Lit.25 mp 123–127 °C).
1H NMR (400 MHz, CDCl3): δ = 12.40 (s, 1 H), 7.33–7.18 (m, 6 H),
6.93 (d, J = 2.1 Hz, 1 H), 6.73 (dd, J = 8.6, 2.1 Hz, 1 H), 6.47 (br s,
1 H),), 4.55 (d, J = 5.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 160.7, 138.3, 135.5, 127.3,
126.35, 126.3, 124.6, 117.5, 117.1, 111.0, 42.1.
HRMS (ESI): m/z [M + Na]+ calcd for C14H12ClNO2 + Na:
284.0449; found: 284.0437.
N-Benzyl-3-hydroxy-2-naphthamide (12)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.12 g (90%); colorless crystals; mp 164 °C.
1H NMR (400 MHz, CDCl3): δ = 11.75 (s, 1 H), 7.78–7.67 (m, 2 H),
7.48–7.28 (m, 8 H), 6.88 (br s, 1 H), 4.72 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 169.6, 156.7, 137.3, 137.1, 129.0,
128.6, 128.5, 128.05, 128.0, 126.8, 126.8, 126.3, 123.9, 116.9,
112.4, 44.0.
N-Benzyl-2-hydroxy-3-nitrobenzamide (7)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.32 g (87%); yellow crystals; mp 122 °C (Lit.23 mp 122 °C).
1H NMR (400 MHz, CDCl3): δ = 12.34 (s, 1 H), 8.50 (dd, J = 7.7,
1.8 Hz, 1 H), 8.27 (dd, J = 8.4, 1.8 Hz, 1 H), 8.12 (br s, 1 H), 7.40–
7.33 (m, 5 H), 7.12 (t, J = 8.1 Hz, 1 H), 4.71 (d, J = 5.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 163.8, 153.5, 139.5, 137.8, 134.8,
128.81, 128.78, 127.72, 127.6, 122.6, 119.9, 44.1.
HRMS (ESI): m/z [M + Na]+ calcd for C14H12N2O4 + Na: 295.0689;
found: 295.0689.
HRMS (ESI): m/z [M + Na]+ calcd for C17H15NO2 + Na: 300.0995;
found: 300.0977.
N-Benzyl-2-hydroxynicotinamide (13)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
111 mg (62%); pale yellow powder; mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 12.85 (s, 1 H), 9.99 (br t, J = 5.4
Hz, 1 H), 8.68 (dd, J = 7.2, 2.2 Hz, 1 H), 7.47 (dd, J = 6.3, 2.2 Hz,
1 H), 7.41–7.37 (m, 5 H), 6.54 (dd, J = 7.2, 6.3 Hz, 1 H), 4.71 (d,
J = 5.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.0, 163.8, 145.5, 138.6, 137.7,
128.6, 127.5, 127.2, 121.4, 108.0, 43.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12N2O2 + Na: 251.0791;
found: 251.0781.
N-Benzyl-2-hydroxy-5-methoxybenzamide (8)
Column chromatography [silica gel, EtOAc–hexane (1:4)], yield:
0.28 g (61%); colorless crystals; mp 90–92 °C.
1H NMR (400 MHz, CDCl3): δ = 11.8 (s, 1 H), 7.39–7.33 (m, 5 H),
7.03 (dd, J = 9.0, 2.9 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 6.87 (d, J =
2.9 Hz, 1 H), 6.71 (s, 1 H), 4.64 (d, J = 5.7 Hz, 2 H), 3.76 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.6, 155.6, 151.8, 137.4, 128.9,
127.91, 127.87, 121.1, 119.3, 114.0, 109.9, 56.1, 43.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H15NO3 + Na: 280.0944;
found: 280.0919.
2-Hydroxy-3-methoxy-N-[1-(naphthalen-1-yl)ethyl]benzamide
(9)
Column chromatography [silica gel, EtOAc–hexane (1:3)]; yield:
0.08 g (44%); colorless crystals; mp 176–180 °C.
N-Benzyl-2-hydroxythiophene-3-carboxamide (14)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
29 mg (33%); colorless crystals; mp 78–80 °C.
IR (KBr): 3313, 3091, 2925, 2852, 1633, 1550, 1453, 1421, 1293,
1057, 827, 720, 696 cm–1.
IR (KBr): 3360, 3054, 2925, 2847, 1638, 1585, 1539, 1462, 1375,
1249, 1061, 777, 739 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1417–1426

1424
S. J. Balkrishna, S. Kumar
PAPER
1H NMR (500 MHz, CDCl3): δ = 7.9 (dd, J = 3.0, 1.3 Hz, 1 H), 7.41
(dd, J = 5.1, 1.3 Hz, 1 H), 7.39–7.31 (m, 6 H), 6.33 (br s, 1 H), 4.60
(d, J = 5.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 162.9, 138.2, 137.3, 128.8, 128.4,
127.9, 127.7, 126.6, 126.0, 43.9.
HRMS (ESI): m/z [M – H]+ calcd for C12H10NO2S: 232.0427;
found: 232.0434.
N,N′-(Ethane-1,2-diyl)bis(2-hydroxybenzamide) (19)
Column chromatography [silica gel, EtOAc–hexane (1:1)]; yield:
0.27 g (77%); colorless crystals; mp 110 °C (Lit.26 mp 111–113 °C).
1H NMR (400 MHz, CDCl3): δ = 8.95 (br t, 2 H), 7.82 (d, J = 8.0
Hz, 2 H), 7.38 (dt, J = 7.7, 1.6 Hz, 2 H), 6.9 (m, 4 H), 3.49 (t, J = 2.6
Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 174.6, 165.3, 138.9, 132.9,
123.7, 122.6, 120.4, 43.8.
N-Benzyl-3-hydroxythiophene-2-carboxamide (15)
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield:
0.157 g (57%); colorless crystals; mp 114–116 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C16H16N2O4 + Na: 323.1002;
found: 323.1027.
1H NMR (400 MHz, CDCl3): δ = 11.20 (s, 1 H), 7.36 (m, 5 H), 7.25
(d, J = 5.4 Hz, 1 H), 6.80 (d, J = 5.4 Hz, 1 H), 6.00 (s, 1 H), 4.60 (d,
J = 5.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 166.0, 163.9, 137.7, 127.85,
127.80, 127.78, 127.3, 120.2, 104.9, 43.4.
HRMS (ESI): m/z [M – H]+ calcd for C12H10NO2S: 232.0427;
found: 232.0426.
N,N′-(Propane-1,3-diyl)bis(2-hydroxybenzamide) (20)
Column chromatography [silica gel, EtOAc–hexane (1:1)]; yield:
0.32 g (72%); colorless crystals; mp 181 °C (Lit.26 mp 181–182 °C).
1H NMR (400 MHz, CDCl3): δ = 12.60 (s, 2 H), 8.87 (t, J = 5.4 Hz,
2 H), 7.84 (dd, J = 7.8, 1.2 Hz, 2 H), 7.38 (t, J = 7.7 Hz, 2 H), 6.90
(t, J = 8.3 Hz, 4 H), 3.4 (t, J = 6.4 Hz, 4 H), 1.84 (quint, J = 7.0 Hz,
2 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.5, 160.5, 134.1, 128.1,
119.0, 117.8, 115.7, 37.2, 29.3.
2-Hydroxy-N-(2-iodophenyl)benzamide (16) from 2-Halo-N-(2-
iodophenyl)benzamide
HRMS (ESI): m/z [M + Na] calcd for C17H18N2O4 + Na: 337.1159;
found: 337.1192.
Column chromatography [silica gel, EtOAc–hexane (1:4)]; yield
starting from 2-iodo-N-(2-iodophenyl)benzamide: 0.345 g (92%),
from 2-bromo-N-(2-iodophenyl)benzamide: 0.30 g (89%), from 2-
chloro-N-(2-iodophenyl)benzamide: 0.57 g (86%) (Scheme 2); col-
orless crystals; mp 137–139 °C.
N,N′-(Hexane-1,6-diyl)bis(2-hydroxy-3-nitrobenzamide) (21)
Column chromatography [silica gel, EtOAc–hexane (3:2)]; yield:
0.14 g (63%); pale yellow crystals; mp 170–172 °C.
IR (KBr): 3420, 2922, 1667, 1614, 1436, 1288, 1247, 1212, 1158,
910, 748, 657 cm–1.
1H NMR (400 MHz, CDCl3): δ = 11.80 (s, 1 H), 8.3 (s, 1 H), 8.23
(dd, J = 8.3, 1.5 Hz, 1 H), 7.78 (dd, J = 8.0, 1.4 Hz, 1 H), 7.60 (dd,
J = 8.0, 1.4 Hz, 1 H),7.40 (m, 1 H) 7.35 (m, 1 H), 6.99 (dd, J = 8.4,
1.0 Hz, 1 H), 6.93 (m, 2 H).
IR (KBr): 3304, 2929, 2853, 1644, 1581, 1524, 1434, 1367, 1285,
741 cm–1.
1H NMR (400 MHz, CDCl3): δ = 14.60 (s, 2 H), 9.25 (t, J = 5.4 Hz,
2 H), 8.18 (dd, J = 8.0, 1.5 Hz, 2 H), 8.10 (dd, J = 8.0, 1.5 Hz, 2 H),
7.06 (t, J = 8.0 Hz, 2 H), 3.33 (q, J = 6.8 Hz, 4 H) (merged with
H2O), 1.60 (m, 4 H), 1.40 (m, 4 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H10INO2: 360.9576; found:
360.3246.
13C NMR (100 MHz, DMSO-d6): δ = 169.1, 155.4, 139.0, 132.7,
129.6, 118.1, 117.6, 39.7, 28.9, 26.5.
2-Hydroxy-N1,N3-bis(1-phenylethyl)isophthalamide (17)
Column chromatography [silica gel, EtOAc–hexane (2:3)]; yield:
0.230 g (84%); colorless crystals; mp 168–170 °C.
HRMS (ESI): m/z [M – H]+ calcd for C20H21N4O8: 445.1354; found:
445.1356.
N,N′-(Cyclohexane-1,2-diyl)bis(2-hydroxybenzamide) (22)
Column chromatography [silica gel, EtOAc–hexane (3:2)]; yield:
0.23 g (74%); colorless crystals; mp 235 °C (Lit.27 mp 238–239 °C).
1H NMR (400 MHz, CDCl3): δ = 12.39 (s, 2 H), 8.64 (d, J = 7.4 Hz,
2 H), 7.77 (d, J = 7.8 Hz, 2 H), 7.34 (dt, J = 7.6, 1.5 Hz, 2 H), 6.84
(m, J = 10.9 Hz, 4 H), 4.03 (m, 2 H), 1.97 (m, 2 H), 1.76 (m, 2 H),
1.52 (m, 2 H), 1.33 (m, 2 H).
IR (KBr): 3311, 3064, 2977, 2930, 1650, 1597, 1580, 1538, 1435,
1365, 1276, 1210, 757, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 14.5 (s, 1 H), 7.95 (d, J = 7.8 Hz,
2 H), 7.41–7.26 (m, 12 H), 6.90 (t, J = 7.8 Hz, 1 H), 5.33 (quint,
J = 7.0 Hz, 2 H), 1.60 (d, J = 7.0 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.9, 160.6, 143.2, 133.1, 128.7,
127.4, 126.1, 118.5, 118.0, 49.4, 22.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H24N2O3 + Na: 389.1860;
13C NMR (100 MHz, DMSO-d6): δ = 168.9, 160.2, 134.0, 128.4,
118.9, 117.6, 115.8, 52.6, 32.0, 25.0.
found: 389.1906.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22N2O4 + Na: 377.1472;
found: 377.1471.
N1,N3-Bis(3,4-dimethoxyphenethyl)-2-hydroxyisophthalamide
(18)
Column chromatography [silica gel, EtOAc–hexane (1:1)]; yield:
0.240 g (80%); colorless crystals; mp 138 °C.
Acknowledgment
Dr. S.K. thanks Department of Science and Technology (DST),
New Delhi and Board of Research in Nuclear Science (BRNS), De-
partment of Atomic Energy, Bombay for funding. Central Instru-
ment facility at IISER Bhopal is thanked for NMR and Mass data
collection. S.J.B. is thankful to IISER Bhopal and University Grant
Commission, New Delhi for a fellowship. S.K. kindly acknow-
ledges one of the reviewers for constructive suggestions.
IR (KBr): 3368, 2928, 1651, 1590, 1515, 1438, 1261, 1233, 1156,
1028, 806, 761 cm–1.
1H NMR (400 MHz, CDCl3): δ = 14.91 (s, 1 H), 8.81 (br t, 2 H),
8.02 (d, J = 7.8 Hz, 2 H), 7.01 (t, J = 7.7 Hz, 1 H), 6.88 (d, J = 9.3
Hz, 4 H), 6.77 (d, J = 7.8 Hz, 2 H), 3.72 (s, 12 H), 3.54 (q, J = 7.9
Hz, 4 H), 2.80 (t, J = 7.0 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.4, 160.1, 149.0, 147.7,
133.1, 132.1, 121.0, 118.7, 113.0, 112.3, 55.9, 55.8, 41.3, 34.8.
HRMS (ESI): m/z [M + Na]+ calcd for C28H32N2O7 + Na: 531.2102;
found: 531.2073.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.omnorinIftangonmSorniuifIatoprtngiSutpor
Synthesis 2012, 44, 1417–1426
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Hydroxylation in Aqueous Medium
1425
US Patent 10/159506 (US 030171593), 2002. (o) Taillefer,
M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F. US
10/159829 (US 030236413), 2002. (p) Taillefer, M.;
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Ouali, A. French
Patent FR 6717 (WO 031101966), 2002.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1417–1426

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© Georg Thieme Verlag Stuttgart · New York