Cu-Mn spinel oxide catalyzed regioselective halogenation of phenols and N-heteroarenes

Article abstract of DOI:10.1021/jo300731z

A novel simple, mild chemo- and regioselective method has been developed for the halogenation of phenols using Cu-Mn spinel oxide as a catalyst and N-halosuccinimide as halogenating agent. In the presence of Cu-Mn spinel oxide B, both electron-withdrawing and electron-donating groups bearing phenols gave monohalogenated products in good to excellent yields with highest para-selectivity. The para-substituted phenol gave monohalogenated product with good yield and ortho-selectivity. N-Heteroarenes such as indoles and imidazoles also gave monohalogenated products with high selectivity. Unlike the copper-catalyzed halogenation, the present method works well with electron-withdrawing group bearing phenols and gives comparatively better yields and selectivity. The Cu-Mn spinel catalyst is robust and reused three times under optimized conditions without any loss in catalytic activity. Nonphenolics did not undergo this transformation.

Full text of DOI:10.1021/jo300731z

Note
pubs.acs.org/joc
Cu−Mn Spinel Oxide Catalyzed Regioselective Halogenation of
Phenols and N-Heteroarenes
,
†
†
†
†
Parvinder Pal Singh,* Thanusha Thatikonda, K. A. Aravinda Kumar, Sanghapal D. Sawant,
‡
∥
§
†
,†
Baldev Singh, Amit Kumar Sharma, P. R. Sharma, Deepika Singh, and Ram A. Vishwakarma*
†Medicinal Chemistry Division, Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research), Jammu 180
01, India
0
‡
Natural Product Chemistry, Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research), Jammu 180 001,
India
§
Pharmacology Division, Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research), Jammu 180 001, India
∥Department of Chemistry, University of Jammu, Jammu-180 006, India
*
S Supporting Information
ABSTRACT: A novel simple, mild chemo- and regioselective method
has been developed for the halogenation of phenols using Cu−Mn spinel
oxide as a catalyst and N-halosuccinimide as halogenating agent. In the
presence of Cu−Mn spinel oxide B, both electron-withdrawing and
electron-donating groups bearing phenols gave monohalogenated
products in good to excellent yields with highest para-selectivity. The
para-substituted phenol gave monohalogenated product with good yield
and ortho-selectivity. N-Heteroarenes such as indoles and imidazoles also
gave monohalogenated products with high selectivity. Unlike the copper-
catalyzed halogenation, the present method works well with electron-
withdrawing group bearing phenols and gives comparatively better yields
and selectivity. The Cu−Mn spinel catalyst is robust and reused three
times under optimized conditions without any loss in catalytic activity.
Nonphenolics did not undergo this transformation.
8
alogenated phenols and heteroarenes are widely used as
synthons for the synthesis of various drugs, insecticides,
electron-rich arenes. More recently, a study by Shen et al. on
halogenations of 2-phenylpyridine reported that copper in the
1
H
herbicides, dyestuffs, etc. Apart from their use as synthons,
presence of MnO favor the halogenation on ortho-position of
2
9 10
phenyl ring. We recently reported a Cu−Mn-based catalyst
for ligand-free Huisgen [3 + 2] cycloaddition reaction.
Moreover, copper−manganese spinels have also attracted
these are also present in large number of biologically active
2
,3
marine natural products. The classical approach for their
synthesis is the direct electrophilic halogenation using
molecular chlorine/bromine. Apart from this, numerous
methods have been developed, but most of the methods
have several drawbacks such as toxic reagents, harsh conditions,
low yields, and low chemo- and regioselectivity. After the
discovery of N-halosuccinimide as halogenating agents,
numerous methods have been developed for the variety of
1
1
4
significant attention for their potential applications in catalysis
12
5
as well as in electrochemical systems. Keeping in mind the
recent finding regarding the catalytic properties of copper and
10−12
4
,5
magnesium-based catalysts,
we have explored Cu−Mn
spinel oxide for halogenation reactions and successfully
developed a mild and regioselective Cu−Mn spinel oxide
catalyzed halogenation method for phenols and N-heteroar-
enes.
substrates utilizing various catalysts such as SiO , HZSM-5,
2
HBF ·Et O, TBAB, SO H-functionalized silica, ammonium
4
2
3
We began our studies by screening a series of Cu−Mn spinel
oxide A−C (variation in their composition) for the
halogenation of phenol using N-chlorosuccinimide (NCS) as
halogenating agent and acetonitrile (ACN) as solvent (results
summarized in Table 1). All the optimization reactions were
performed in 1 mmol scale. Among the three Cu−Mn spinel
oxides used, 10% weight equivalent of Cu−Mn spinel oxide (B)
5,6
acetate, and p-TSA. In the past decade, several palladium-
catalyzed regioselective halogenation methods have been
developed, but these methods are either limited to specific
substrates (such as amides, pyridines, pyrimidine, carboxylic
acids, and oxazolines) or require expensive reagents. In recent
years, copper salts have been also utilized as catalysts for the
regioselective halogenation of several arenes and heteroarenes
7
7
8
such as phenol, aniline, etc. Literature survey on copper-
catalyzed halogenation of phenol/aniline revealed that in spite
of high yield and regioselectivity, this method is limited only to
Received: April 18, 2012
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo300731z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Screening of Different Copper-Based Catalysts for
Regioselective Halogenations
that mediated the reaction and provided regioselectivity. In
order to understand the efficiency and catalytic activity as a
function of overall composition, powder X-ray diffraction
f
a
product composition (%)
(
Figure S1, Supporting Information (SI)) and specific surface
temp
time
(h)
2,4-
area (Table S1, SI) of the catalysts were studied. Among the
three Cu−Mn spinel oxide (A−C) with varying amount of
copper (Table S1, SI), the best conversion was observed in
Cu−Mn spinel oxide (B). XRD of Cu−Mn spinel oxide (B)
shows the presence of distinct Mn−Cu phases with
comparatively less intensity of tenorite. On the other hand,
Cu−Mn spinel oxide (C) having more intensity of tenorite and
very small amount of Mn−Cu phases showed no activity
b
entry
a
catalyst
qty
(°C)
S
4-Cl 2-Cl DiCl
c
Cu−Mn
10
10
10
10
10
20
5
80
80
80
80
80
80
80
80
10
10
10
10
08
10
10
10
26
60
70
61
70
80
54
68
53
10
3
8
3
12
3
(A)
c
b
c
d
e
f
Cu−Mn
B)
7
25
3
(
c
d
e
e
e
e
Cu−Mn
C)
(
Cu−Mn
B)
2
21
3
(
(
Figure S1, SI). Further, Cu−Mn spinel oxide (A) and (B)
Cu−Mn
B)
9
2
9
contain the same type of phases (Table S1, SI), but spinel oxide
(B) possesses comparatively less intensity of tenorite. These
results suggested that presence of tenorite (CuO) greatly affects
the yield and selectivity. The presence of distinct Mn−Cu
phases in the form of near spherical nanoparticles (Figure S3,
SI) and comparatively larger surface area (Table S2, SI) of Cu−
Mn spinel oxide (B) might be responsible for enhanced yield
and selectivity. The optimization results suggested that 10%
weight equivalent of Cu−Mn spinel oxide (B) and 0.9 mmol of
NCS per 1 mmol of phenol is the best condition.
(
Cu−Mn
B)
24
13
28
9
(
g
h
Cu−Mn
B)
6
8
(
Cu−Mn
B)
1
5
10
(
i
80
rt
10
36
20
33
45
40
33
27
e
J
Cu−Mn
B)
10
(
k
rt
80
80
80
80
36
10
10
10
10
35
17
18
50
33
42
43
44
25
49
23
32
34
20
13
e
e
e
e
In order to see the diversity, tolerability, and feasibility of
different functionalities, various substituted phenols were
studied under optimized conditions (Table 2). All the
experiments were performed without catalyst for comparative
study, and results are summarized in Table 2. Both electron-
donating group (EDG) and electron-withdrawing group
(EWG) bearing phenol gave good to excellent yield as
monochlorinated product (Table 2, entries b−j). Among
EDG-bearing phenols, 2-methylphenol under optimized
conditions provided the 4-chloro-2-methylphenol 5b in high
yields with 85% selectivity as compared to reaction performed
without catalyst, which gave a mixture of 46% 4-chloro-2-
methylphenol 5b and 38% 6-chloro-2-methylphenol (Table 2,
entry b). The phenol possessing group at para-position also
underwent chlorination smoothly and gave ortho-chlorinated
product with good yield and selectivity (Table 2, entries c, h−
j). 4-Methylphenol gave 80% 2-chloro-4-methylphenol 5c
(Table 2, entry c).
Further, phenol bearing EWGs such as chloro, nitro, formyl,
and acetyl groups (Table 2, entries d−i) gave better yields and
para-selectivities (if para-position is free) as compared to EDG
bearing phenols. The present method is also suitable for double
bond bearing substrates. Eugenol possessing para-allyl group
also underwent chlorination reaction and gave o-chlorinated
product 5j with 86% selectivity (Table 2, entry j). The
effectiveness of the present method is further revealed in the
reaction of several N-heteroarenes and 2-naphthol (result
summarized in Table 3). Indole 3a and 5-nitroindole 3b under
optimized condition gave 3-chlorosubstituted product 7a and
7b with 82 and 86% selectivity, respectively. But in the absence
of catalyst, a substantial quantity of dichlorinated product along
with unreacted starting material were observed (Table 3, entries
a and b). Similarly, imidazole 4a gave monochloro product 8a
with 83% selectivity as compared to uncatalyzed reaction
(Table 3, entry c). The sterically hindered 2-naphthol 2a also
gave monochlorinated product 9a with 89% selectivity as
compared to uncatalyzed reaction (Table 3, entry d).
1
Cul
10
10
10
10
m
n
o
Cu O
2
Cu(OAc)2
CuCl2
4
a
b
The products were characterized by GC−MS. Catalyst wt % equiv
c
w.r.t. phenol. Reaction condition: Phenol (1 mmol) and NCS (1
mmol) in ACN. Reaction condition: Phenol (1 mmol) and NCS (1.2
mmol) in ACN. Reaction condition: Phenol (1 mmol) and NCS (0.9
mmol) in ACN. The number in the product composition denotes the
d
e
f
position of chlorination w.r.t. −OH group. S refers to the substrate and
Cu−Mn (A) = (Cu/Mn 2:0.25), Cu−Mn (B) = (Cu/Mn 1:0.25),
Cu−Mn (C) = (Cu/Mn 3:0.25).
at 80 °C gave p-chlorophenol 5a with 70% selectivity along
with 3% of o-chlorophenol and 12% of dichlorophenol (Table
1, entry b). The composition of products was determined by
GC−MS. Variation in the amount of NCS greatly affected the
yields and selectivity (Table 1, entries d and e). Increase in the
amount of NCS led to greater byproduct formation (Table 1,
entry d), but 0.9 mmol of NCS per 1 mmol of phenol in the
presence of 10 wt % equiv of Cu−Mn spinel oxide B at 80 °C
increased the yield of 5a from 70 to 80% and suppressed the
formation of dichlorophenol from 12 to 3% (Table 1, entry e).
Further, considering this best condition, the effect of amount of
catalyst and temperature on this transformation was also
evaluated (Table 1, entries f−k). An increase or decrease in the
amount of Cu−Mn spinel oxide B did not provide a significant
effect toward yield and selectivity (Table 1, entries f−h), but
there was substantial loss in the yield and selectivity when
reaction was performed at room temperature (Table 1, entry j).
Further, no selectivity was observed even when the reactions
were performed without Cu−Mn spinel oxide (B) at 80 °C and
at room temperature, respectively (Table 1, entries i and k),
suggesting that Cu−Mn spinel oxide might interact and activate
the substrate at higher temperature, and therefore enhanced
yield and para-selectivity was observed. We further screened
other copper salts, viz., CuI, Cu O, Cu(OAc) , CuCl , in order
2
2
2
to find whether these Cu salts catalyze this reaction, but none
of these gave selectivity (Table 1, entries l−o). These findings
suggested that it was not the copper but Cu−Mn spinel oxide
In order to further know the diversity of present method, the
bromination with N-bromosuccinimide (NBS) was also
explored with various unsubstituted and substituted phenols.
B
dx.doi.org/10.1021/jo300731z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 2. Cu−Mn Spinel Oxide (B) Catalyzed Regioselective
Table 3. Cu−Mn Spinel Oxide (B) Catalyzed Regioselective
Chlorination/Bromination of Naphthol and N-
Heteroarenes
c
Chlorination of Phenols
c
a
b
The products were characterized by GC−MS. Isolated yields of
c
major products are provided in the Experimental Section. Reaction
condition (A): Phenol (1 mmol), NCS (0.9 mmol), 10 wt % equiv of
Cu−Mn spinel oxide (B) w.r.t. phenols/N-heteroarenes at 80 °C.
Reaction condition (B): Phenol (1 mmol), NCS (0.9 mmol) at 80 °C.
Reaction condition (D): Phenol (1 mmol), NBS (1 mmol), 10 wt %
equiv of Cu−Mn spinel oxide (B) w.r.t. phenols/N-heteroarenes at 80
°C. Reaction condition (E): Phenol (1 mmol), NBS (1 mmol) at 80
a
b
The products were characterized by GC−MS. Isolated yields of
c
major products are provided in the Experimental Section. Reaction
condition (A): Phenol (1 mmol), NCS (0.9 mmol), 10 wt % equiv of
Cu−Mn spinel oxide (B) w.r.t. phenol at 80 °C. Reaction condition
°
C. P refers to major product. S refers to the substrate.
(
(
B): Phenol (1 mmol), NCS (0.9 mmol) at 80 °C. Reaction condition
C): Phenol (1 mmol), NCS (0.9 mmol), 10 wt % equiv of Cu−Mn
In order to see the robustness of this Cu−Mn spinel oxide
spinel oxide (B) w.r.t. phenol at rt. The number in the product
composition denotes the position of chlorination w.r.t. −OH group. S
refers to the substrate.
(B) catalyst, we carried out the reusability study with 2-
formylphenol (Table 5). The Cu−Mn spinel oxide (B) was
recovered by filtration after each experiment and could be
reused for chlorination of phenol in three successive reactions
without significant loss of the catalytic activity. A SEM image of
used bimetallic catalyst shows that the morphology and the
structural integrity of the Cu−Mn spinel oxide (B) remain
same at the end of third run. This finding suggested that Cu−
Mn spinel (B) is robust and was not affected under the reaction
conditions.
Phenol on reaction with NBS at 80 °C gave mixture of mono-
and dibrominated product along with 33% unreacted phenol,
while in the presence of Cu−Mn spinel oxide (B), the
selectivity toward the formation the para-bromophenol 6a
increased from 29 to 74% (Table 4, entry a). Similarly, in the
presence of Cu−Mn spinel oxide (B)/NBS, EDG (such as o-
methyl), and EWG (o-formyl, o-acetyl) bearing phenol also
underwent bromination with excellent selectivity as compared
to experiment performed without catalyst (Table 4, entries b−
d). The sterically hindered phenol 1e did not give brominating
product in the absence of Cu−Mn spinel oxide (B), but in the
presence of catalyst, it underwent bromination and gave o-
brominated product 6e with 90% selectivity (Table 4, entry e).
The bromination of naphthol also underwent smoothly and
gave monobromo-product 10a with 84% selectivity (Table 3,
entry e).
The present halogenation method was also tried for
iodination with N-iodosuccinimide (NIS), but it did not give
good selectivity; however, the mixture of mono, di, and other
products were obtained. Further, regioselective halogenation
was not achieved in nonphenolic compounds such as anisole
and nitrobenzene, which suggested that the present method is
specific to phenols and N-heterocycles.
Although the mechanism of present method cannot be
clearly explained, some assumptions could be made on the basis
of the available information. The applicability of present
method toward EWG-bearing phenols suggests that it might
not operate through free-radical mechanism, which is normally
proposed for copper-catalyzed regioselective oxyhalogenation
8
of phenols/anilines. The above finding was confirmed when
present halogenation method underwent smoothly in the
presence of free-radical scavenger such as (2,2,6,6-tetramethyl-
piperidin-1-yl)oxyl (TEMPO) and ruled out the possibility of
involvement of free radical mechanism. Our careful examina-
11c
tion of literature regarding catalysis of Cu−Mn spinel and
13
other related bimetallic spinel revealed that their catalytic
activity and selectivity largely depends on acid−base properties
as well as both structure of catalyst and orientation of substrate.
On the basis of literature reports, we speculate that phenolate
and aromatic interact with Cu−Mn spinel having an orientation
that favors the para-selectivity. It is further assumed that Cu−
C
dx.doi.org/10.1021/jo300731z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 4. Cu−Mn Spinel Oxide (B) Catalyzed Regioselective
EXPERIMENTAL SECTION
■
c
Bromination of Phenols
Preparation of Cu−Mn Spinel Oxide (A−C). A series of
copper−manganese mixed oxides (A−C) were prepared by the
coaddition of the aqueous solutions of CuCl ·2H O and MnCl ·4H O
2
2
2
2
in a molecular weight ratio (2:0.25; 1:0.25; 3:0.25, respectively) at a
−1
rate of 1 mL min under vigorous mechanical stirring at room
temperature to form a uniform solution. Then ammonia solution was
added drop by drop until it reached pH 8.5−8.7 and was allowed to
stand overnight to form a gel, filtered, and washed with double distilled
water until free from chloride ions. After being kept overnight at room
temperature, the cake was allowed to dry in an air oven at 110 °C for
−
1
2
4 h and finally calcined (10 °C min ) in a muffle furnace at 425 °C
for 3 h.
9
Catalysts were adequately characterized as reported previously to
understand the efficiency of catalytic activity. X-ray diffraction (XRD),
specific surface area, and scanning electron micrograph (SEM) were
studied and are provided in the Supporting Information.
General Procedure for Cu−Mn Spinel Oxide (B) Catalyzed
Chlorination of Phenols/N-Heteroarenes. Substrate (1 mmol)
was dissolved in acetonitrile (5 mL), and then bimetallic catalyst (Cu−
Mn spinel oxide B, 10 wt % equiv) was added. The reaction mixture
was heated and stirred at 80 °C for 10 min followed by slow addition
of NCS (0.9 mmol). Heating was continued at 80 °C for the required
time (Tables 2 and 3). After completion of reaction as indicated by
TLC, the reaction mixture was filtered, and the filtrate was washed
with ethyl acetate (5 mL × 3). The bimetallic catalyst was washed
twice with ethyl acetate (5 mL × 2). The combined organic portion
was dried over anhydrous Na SO . The solvent was removed by
a
b
The products were characterized by GC−MS. Isolated yields of
c
major products are provided in the Experimental Section. Reaction
condition (D): Phenol (1 mmol), NBS (1 mmol), 10 wt % equiv of
Cu−Mn spinel oxide (B) w.r.t. phenol at 80 °C. Reaction condition
2
4
evaporation under reduced pressure to afford the crude product, which
was analyzed by GC−MS to determine the product composition
(
E): Phenol (1 mmol), NBS (1 mmol) at 80 °C. The number in the
(given in Table 2 and 4). The crude product was then subjected to
product composition denotes the position of bromination w.r.t. −OH
group. S refers to the substrate.
column chromatography (hexane/ethyl acetate as eluent) for final
purification to isolate the respective major product. The products
reported herein are characterized by NMR and GC−MS, and their
b
5
,7,14
Table 5. Reusability of Cu−Mn Spinel Oxide (B)
values are in agreement with those reported in the literature.
5,14a
4
-Chlorophenol 5a
(Table 2, entry a). Data: TLC (EtOAc/
hexane 2:8) R = 0.45; Isolated yield 98.56 mg (77%); H NMR (400
1
f
MHz, CDCl ) δ 5.06 (s, 1H), 6.75−6.78 (d, J = 9.03 Hz, 2H), 7.18−
3
7
.20 (d, J = 9.03 Hz, 2H); GC−MS (EI) m/z (relative intensity) 130.1
+
+
(M +2, 29.8), 128.2 (M , 99.8), 92.0 (1.88), 63.1 (10.06).
14b
4
-Chloro-2-methylphenol 5b
(Table 2, entry b). Data: TLC
1
(EtOAc/hexane 2:8) R = 0.25; Isolated yield 115.02 mg (81%); H
f
NMR (400 MHz, CDCl ) δ 2.21 (s, 3H), 4.95 (s, 1H), 6.68−6.70 (d, J
3
=
8.49 Hz, 1H), 7.01−7.03 (dd, J = 2.15, 8.46 Hz, 1H), 7.09 (d, J =
a
b
+
The products were characterized by GC−MS. Reaction condition
1.88 Hz, 1H); GC−MS (EI) m/z (relative intensity) 144.0 (M +2,
17.13), 142.1 (M , 54.92), 107.1 (99.98), 89.0 (13.79), 77.0 (44.77),
63.0 (7.04), 51.0 (9.92).
+
(
A): Phenol (1 mmol), NCS (0.9 mmol), 10 wt % equiv of Cu−Mn
spinel oxide (B) w.r.t. phenols/N-heteroarenes at 80 °C. S refers to the
5,14c
substrate.
2-Chloro-4-methylphenol 5c
(Table 2, entry c). Data: TLC
1
(EtOAc/hexane 2:8) R = 0.38; Isolated yield 68.16 mg (48%); H
f
NMR (400 MHz, CDCl ) δ 2.31 (s, 3H), 5.80 (s, 1H), 6.98 (m, 2H),
Mn spinel might also activate NCS/NBS to release chlorinium/
brominium ion, which ultimately undergoes halogenation.
In summary, we have presented a new method for
regioselective mono chlorination/bromination of phenols and
N-heteroarenes in the presence of robust and reusable
bimetallic Cu−Mn spinel oxide catalyst using simple and
inexpensive N-halosuccinimides as halogenating agent. The
present method is very general and is applicable to both EDG-
and EWG-bearing phenols. Moreover, in the present method
EWG-bearing phenols gave comparatively better results in
terms of yield and selectivity. The present method is also
suitable for various N-heteroarenes such as indole and
imidazole. These transformations provide regioselectively for
chlorination and bromination to a wide array of phenols and N-
heteroarenes. Further exploration for full scope of these
reactions and its extension to other arenes and heteroarenes
as well as mechanistic study is underway and will be reported in
due course.
3
+
7
1
.21 (m, 1H); GC−MS (EI) m/z (relative intensity) 144.1 (M +2,
+
3.37), 142.1 (M , 47.43), 107.1 (99.99), 79.1 (12.29).
14a
2
,4-Dichlorophenol 5d and 5h
(Table 2, entries d and h).
Data: TLC (EtOAc/hexane 2:8) R = 0.31; Isolated yield 126.36 mg
f
1
(
78% for 5d) and 123.50 (76% for 5h); H NMR (400 MHz, CDCl )
3
δ 6.93−6.95 (d, J = 8.79, 1H), 7.13−7.15 (dd, J = 2.51, 8.54 Hz, 1H),
7.31−7.32 (d, J = 2.63, 1H); GC−MS (EI) m/z (relative intensity)
+
+
164.0 (M +2, 10.53), 162.2 (M , 99.95), 126.2 (20.08), 99.0 (13.73),
73.1 (5.71), 63.1 (60.27), 53.1 (6.58).
14d
4
-Chloro-2-nitrophenol 5e
EtOAc/hexane 2:8) R = 0.39; Isolated yield 138.40 mg (80%); H
(Table 2, entry e). Data: TLC
1
(
f
NMR (400 MHz CDCl ) δ 7.13−7.15 (d, J = 8.62 Hz, 1H), 7.53−7.56
3
(
(
(
(
d, J = 9.54 Hz, 1H), 8.11 (s, 1H), 10.48 (s, 1H); GC−MS (EI) m/z
+
+
relative intensity)174.9 (M +2, 33.9), 173.0 (M , 99.93), 157.0
10.4), 143.1 (44.04), 128.1 (10.10), 115.1 (66.14), 99.0 (45.67), 73.0
16.17), 63.0 (69.49), 52.9 (10.56).
14e
4
-Chloro-2-formylphenol 5f
(Table 2, entry f). Data: TLC
1
(EtOAc/hexane 2:8) R = 0.41; Isolated yield 124.80 mg (80%); H
f
NMR (400 MHz, CDCl ) δ 6.96−6.98 (d, J = 8.53 Hz, 1H), 7.46−
3
D
dx.doi.org/10.1021/jo300731z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7
.49 (dd, J = 2.38, 9.67 Hz, 1H), 7.53−7.57 (d, J = 3.01 Hz, 1H), 9.85
characterized by NMR and GC−MS and their values are in agreement
1
5
(
(
(
s, 1H), 10.92 (s, 1H); GC−MS (EI) m/z (relative intensity) 158.2
with those reported in the literature.
+
+
15a
M +2, 31.71), 156.2 (M , 99.98), 127.5 (12.81), 99.1 (25.49), 74.2
6.24), 63.2 (30.28).
4-Bromophenol
hexane 3:7) R = 0.35; Isolated yield 122.12 mg (71%); H NMR (400
MHz CDCl ) δ 4.96 (s, 1H), 6.71−6.73 (dd, J = 2.17, 6.81 Hz, 2H),
6a (Table 4, entry a). Data: TLC (EtOAc/
1
f
1
4f,g
2
-Acetyl-4-chlorophenol 5g
(Table 2, entry g). Data: TLC
3
1
(
EtOAc/hexane 2:8) R = 0.32; Isolated yield 120.70 mg (71%); H
7.32−7.34 (dd, J = 2.08, 6.72 Hz, 2H); GC−MS (EI) m/z (relative
f
+
+
NMR (400 MHz, CDCl ) δ 2.61 (s, 3H), 6.93−6.95 (d, J = 8.8 Hz,
intensity) 174.1 (M +2, 97.59), 172.0 (M , 99.99), 131.2 (5.54), 63.1
(21.15).
3
1
1
1
H), 7.40−7.43 (dd, J = 2.56, 8.62 Hz, 1H), 7.69−7.70 (d, J = 2.56 Hz,
15b
+
4
-Bromo-2-methylphenol
EtOAc/hexane 3:7) R = 0.35; Isolated yield 135.78 mg (73%); H
6b (Table 4, entry b). Data: TLC
H), 12.14 (s, 1H); GC−MS (EI) m/z (relative intensity) 172 (M +2,
1
+
(
7.5), 170 (M , 96.36), 155.4 (100), 99.0 (4.72), 63.1 (9.62).
f
1
4g
NMR (400 MHz CDCl ) δ 2.22 (s, 3H), 5.05 (s, 1H), 6.64−6.66 (d, J
4
-Acetyl-2-chlorophenol 5i
(Table 2, entry i). Data: TLC
3
1
= 8.47 Hz, 1H), 7.15−7.18 (dd, J = 2.27, 8.48 Hz, 1H), 7.23−7.24 (d, J
(
EtOAc/hexane 2:8) R = 0.38; Isolated yield 134.30 mg (79%); H
f
+
=
7
2.01 Hz, 1H); GC−MS (EI) m/z (relative intensity) 190.0 (M +2,
NMR (500 MHz CDCl ) δ 2.56 (s, 3H), 6.05 (s, 1H), 7.07−7.09 (d, J
=
3
+
3.26), 188.0 (M , 74.66), 107.1 (99.99), 77.1 (74.49), 51.0 (15.6).
8.51 Hz, 1H), 7.81−7.84 (dd, J = 1.78, 8.76 Hz, 1H), 7.99 (d, J =
15c
+
4-Bromo-2-formylphenol
6c (Table 4, entry c). Data: TLC
1
1
6
6
.96 Hz, 1H); GC−MS (EI) m/z (relative intensity) 172.0 (M +2,
+
(EtOAc/hexane 3:7) R = 0.37; Isolated yield 156.00 mg (78%); H
.05), 170.0 (M , 17.25), 155.1 (99.94), 127.2 (19.00), 99.0 (24.56),
f
NMR (400 MHz CDCl ) δ 6.90−6.92 (d, J = 8.87 Hz, 1H), 7.59−7.62
3.0 (17.58), 51.0 (3.11).
3
7
b,c
(dd, J = 2.47, 8.87 Hz, 1H), 7.68 (d, J = 2.32 Hz, 1H), 9.84 (s, 1H),
4
-Allyl-2-chloro-6-methoxy phenol 5j
(Table 2, entry j). Data:
+
1
0.93 (s, 1H); GC−MS (EI) m/z (relative intensity) 202.2 (M +2,
TLC (EtOAc/hexane 2:8) R = 0.41; Isolated yield 158.40 mg (80%);
f
+
1
95.65), 200.1 (M , 99.96), 182.1 (7.01), 156.1 (7.44), 143.1 (12.96),
2.1 (5.52), 75.1 (6.02), 63.1 (33.13).
6d (Table 4, entry d). Data: TLC
EtOAc/hexane 3:7) R = 0.34; Isolated yield 164.78 mg (77%); H
H NMR (400 MHz, CDCl ) δ 3.24−3.29 (m, 2H), 3.88 (s, 3H),
3
9
5
1
2
1
6
.06−5.10 (d, J = 15.01 Hz, 2H), 5.73−5.80 (m, 1H), 5.84−5.96 (m,
15d
2
-Acetyl-4-bromo-phenol
H), 6.59 (s, 1H), 6.77 (s, 1H); GC−MS (EI) m/z (relative intensity)
00.0 (M +2,32.29), 198.0 (99.99), 183.0 (17.20), 163.1 (21.36),
31.1 (54.50), 119.1 (51.78), 103.1 (67.46), 91.0 (51.78), 77.0 (7.52),
3 (10.17), 51.0 (4.76).
1
(
+
f
NMR (400 MHz CDCl ) δ 2.63 (s, 3H), 6.89−6.91 (d, J = 8.89 Hz,
3
1
1
4
6
H), 7.54−7.56 (dd, J = 2.42, 8.89 Hz, 1H), 7.84 (d, J = 2.42 Hz, 1H),
+
2.16 (s, 1H); GC -MS (EI) m/z (relative intensity) 216.0 (M +2,
1
4h
3
-Chloro-1H-indole 7a (Table 3, entry a). Data: TLC (EtOAc/
+
4.30), 214.0 (M , 48.9), 199.1 (99.98), 143.1 (14.36), 89.1 (5.94),
1
hexane 2:8) R = 0.32; Isolated yield 117.78 mg (78%); H NMR (400
MHz, CDCl ) δ 7.09−7.12 (t, J = 7.73 Hz, 1H), 7.16−7.20 (t, J = 8.04
Hz, 1H), 7.41−7.43 (d, J = 8.13 Hz, 1H),7.47−7.53 (m, 2H), 11.34
f
3.1 (24.82), 43.0 (10.61).
15e
3
3
-Bromo-2-hydroxy-4,5-dimethoxybenzaldehyde 6e (Table 4,
entry e). Data: TLC (EtOAc/hexane 3:7) R = 0.36; Isolated yield
2
f
+
(
1
(
brs, 1H); GC−MS (EI) m/z (relative intensity) 153.0 (M +2, 30.11),
1
23.60 mg (86%); H NMR (400 MHz CDCl ) δ 3.89 (s, 3H), 4.00
3
+
51.2 (M , 99.98), 123.4 (6.69), 116.4 (18.40), 89.1 (49.96), 63.1
8.39).
-Chloro-5-nitro-1H-indole 7b (Table 3, entry b). Data: TLC
(
(
2
s, 3H), 7.02 (s, 1H), 9.75 (s, 1H), 11.57 (s, 1H); GC−MS (EI) m/z
+
+
relative intensity) 264.1 (M +2, 26.11), 262.0 (M +2, 30.11),
1
4i
3
+
62.1(M , 97.46), 245.2 (13.68), 217.2 (5.86), 189.2 (6.47), 137.2
1
(
(
8
EtOAc/hexane 3:7) R = 0.36; Isolated yield 158.76 (81%); H NMR
400 MHz CDCl ) δ 7.62 (d, J = 9.04 Hz, 1H), 7.85 (s, 1H), 8.06−
.09 (dd, J = 2.27, 9.03 Hz, 1H), 8.32−8.40 (d, J = 2.04 Hz, 1H), 12.12
f
(17.11), 110.2 (49.11), 95.1 (6.40), 79.2 (6.52), 53.1 (10.95).
1
5a
3
1-Bromo-2-napthol
10a (Table 3, entry e). Data: TLC
1
(EtOAc/hexane 3:7) R = 0.37; Isolated yield 175.38 mg (79%); H
f
+
(
1
(
brs, 1H); GC−MS (EI) m/z (relative intensity) 198.0 (M +2, 30.16),
96.1 (99.99), 180 (14.87), 166.1 (62.04), 150.1 (21.56), 138.1
26.76), 123.1 (37.20), 115.2 (17.0), 87.1 (13.40).
NMR (400 MHz CDCl ) δ 5.91 (s, 1H), 7.26−7.29 (m, 1H
3
submerged with solvent peak), 7.38−7.42 (t, J = 7.14 Hz, 1H), 7.55−
7.59 (t, J = 7.30 Hz, 1H), 7.74−7.76 (d, J = 8.83 Hz, 1H), 7.78−7.80
(d, J = 8.18 Hz, 1H), 8.02−8.04 (d, J = 8.48 Hz, 1H); GC−MS (EI)
1
4j
4
-Chloro-1H-imidazole
8a (Table 3, entry c). Data: TLC
1
+
+
(
EtOAc/hexane 3:7) R = 0.39; Isolated yield 80.58 mg (79%); H
m/z (relative intensity) 224.2 (M +2, 90.00), 222.1 (M , 99.93), 195.0
f
NMR (200 MHz CDCl ) δ 6.99 (s, 1H), 7.57 (s, 1H); GC−MS (EI)
(6.05), 143.1 (5.84), 115 (89.85), 87.0 (15.76), 63 (13.49).
3
+
+
m/z (relative intensity) 104.0 (M +2, 31.08), 102.0 (M , 99.85), 75.0
(
35.25), 48.0 (12.66), 40.0 (12.01).
ASSOCIATED CONTENT
Supporting Information
Characterization data of Cu−Mn spinel oxide along with H
NMRs and GC−MS of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
4k,l
■
1
-Chloro-2-naphthol
9a (Table 3, entry d). Data: TLC
*
S
1
(
(
EtOAc/hexane 2:8) R = 0.32; yield 151.30 mg (85%); H NMR
f
1
400 MHz, CDCl ) δ 5.89 (s, 1H), 7.25−7.27 (m, peak merged with
3
CDCl , 1H), 7.38−7.42 (t, J = 7.28 Hz, 1H), 7.55−7.59 (t, J = 7.13
3
Hz, 1H), 7.70−7.72 (d, J = 8.89 Hz, 1H), 7.78−7.80 (d, J = 8.17
Hz,1H), 8.05−8.07 (d, J = 8.49 Hz, 1H); GC MS (EI) m/z (relative
+
+
AUTHOR INFORMATION
Corresponding Author
Tel.: +91-191-2569111. Fax: +91-191-2569333. E-mail:
ppsingh@iiim.res.in; ram@iiim.res.in. IIIM communication
No. IIIM/1473/2012.
intensity) 180.1 (M +2, 31.3), 178.3 (M , 99.9), 149.4 (9.08), 114.4
■
*
(
35.59), 87.1 (7.30), 63.1 (5.20).
General Procedure for Cu−Mn Spinel Oxide (B) Catalyzed
Bromination of Phenols/N-Heteroarenes. Substrate (1 mmol)
was dissolved in acetonitrile (5 mL), and then bimetallic catalyst (Cu−
Mn spinel oxide B, 10 wt % equiv) was added. The reaction mixture
was heated and stirred at 80 °C for 10 min followed by slow addition
of NBS (0.9 mmol). Heating was continued at 80 °C for the required
time (Tables 3 and 4). After completion of reaction as indicated by
TLC, the reaction mixture was filtered, and the filtrate was washed
with ethyl acetate (5 mL × 3). The bimetallic catalyst was washed
twice with ethyl acetate (5 mL × 2). The combined organic portion
was dried over anhydrous Na SO . The solvent was removed by
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.T. thanks CSIR and K.A.A.K. thanks UGC for Research
Fellowship. Authors are thankful for the support from
Instrumentation Division of IIIM-J.
2
4
evaporation under reduced pressure to afford the crude product, which
was analyzed by GC−MS and NMR spectroscopic methods to
determine the product composition (given in Tables 3 and 4). The
crude product was then subjected to column chromatography
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