Reductive dehalogenation of aryl bromides and chlorides and their use as aryl blocking groups

Article abstract of DOI:10.1055/s-0029-1217112

Bromo and chloro substituents serve as excellent blocking groups on aromatic rings. When a halo substituent is para to an ortho,para-directing group, the ortho positions can be easily functionalized, and the halo group can be subsequently removed by catalytic hydrogenation under neutral conditions. As expected, bromides are reduced more quickly than chlorides and the reaction requires the use of less catalyst. Bromides can be selectively reduced in the presence of nitro, chloro, cyano, keto, or carboxylic acid groups. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217112

PAPER
217
Reductive Dehalogenation of Aryl Bromides and Chlorides and Their Use as
Aryl Blocking Groups
R
A
eductive Dehalog
h
enation of
A
a
ryl
B
romid
l
es and
y
Chloride
s
a Ramanathan, Leslie S. Jimenez*
Department of Chemistry & Chemical Biology, Rutgers, The State University of New Jersey,
10 Taylor Road, Piscataway, NJ 08854–8087, USA
6
Fax +1(732)4455312; E-mail: Leslie.Jimenez@rutgers.edu
Received 7 August 2009; revised 30 September 2009
carbon-catalyzed reduction with formate salts gives good
yields of dehalogenated products.9
Abstract: Bromo and chloro substituents serve as excellent block-
ing groups on aromatic rings. When a halo substituent is para to an
ortho,para-directing group, the ortho positions can be easily func- Aryl bromo groups can be selectively reduced in the pres-
tionalized, and the halo group can be subsequently removed by cat-
ence of chloro substituents by treatment with zinc in a ba-
alytic hydrogenation under neutral conditions. As expected,
bromides are reduced more quickly than chlorides and the reaction
requires the use of less catalyst. Bromides can be selectively re-
duced in the presence of nitro, chloro, cyano, keto, or carboxylic
acid groups.
10
sic solution, a homogenous palladium(0) catalyst with
11
poly(methylhydrosiloxane) as a hydrogen donor, or
1
gen.
0% palladium-on-carbon under an atmosphere of hydro-
1
2
Key words: arenes, halides, hydrogenation, reductions, regioselec- Conditions for reducing aryl chlorides are generally more
tivity
vigorous than those required for bromides. Photolysis of
chlorophenols in an alcohol solvent leads to the dehaloge-
13
nated products. Chloroanilines can be reduced by a for-
14
Regioselective synthesis of ortho-substituted benzenes mate hydrogen donor and a palladium catalyst. Sodium
can be achieved through the use of a blocking group at the hypophosphite15 and sodium borohydride can also be
para position. Functionalization at one or both ortho po- used as hydrogen donors to reduce chlorobenzenes. Hy-
sitions, followed by removal of the blocking group, yields drogenation with a polymer-supported palladium catalyst
the corresponding ortho-substituted aromatic compound has shown some degree of regioselectivity in the reduc-
16
1
7
(
Scheme 1). Sulfonic acids have long been used as para- tion of polychlorinated benzenes. Hydrodehalogenation
1
blocking groups, but this method is not compatible with with palladium-on-carbon and dihydrogen in a multiphase
acid-sensitive functional groups. tert-Butyl groups can system reduces polychlorinated benzenes rapidly and
also be used as positional protective groups on phenyl completely.18 Triethylamine selectively enhances the ac-
rings, but their removal also requires acidic conditions.2 tivity of palladium-on-carbon catalysts for the reduction
Current methods of ortho-substitution are limited to par- of aryl chlorides relative to other sensitive functional
3
19
ticular types of substrates and substituents.
groups; however, a nitro group was reduced under these
conditions.
R1
R1
R1
R1
Hydrogen gas is attractive as a hydrogen donor because of
its relatively low price and ease of use, which make it the
R2
R2
20
reductant of choice for industrial applications. We have
found that the selective hydrogenolysis of aryl halides at
atmospheric pressure is possible in the presence of a num-
ber of other functional groups if 10 wt% palladium-on-
carbon is used as the catalyst.
X
X
X = Br or Cl
Scheme 1
To illustrate the principle of using aryl halides as blocking
groups, a series of readily available bromo- and chloro-
benzenes was reduced by catalytic hydrogenation
A wide variety of methods are available for reducing aryl
bromides. The reversibility of electrophilic bromination
4
(
Scheme 2 and Table 1). For bromides, the use of 0.6
on activated arenes (e.g., anilines, phenols, or anisoles)
means that the equilibrium can be shifted towards the de-
brominated product in the presence of a bromine scaven-
ger such as sodium sulfite, toluene, or aniline. Aryl
bromides can also be reduced by lithiation and subsequent
mol% of 10 wt% palladium-on-carbon in methanol was
sufficient to remove the halide at room temperature within
one hour. Three equivalents of sodium bicarbonate were
added to neutralize the hydrogen bromide byproduct. In
the presence of other easily reducible substituents, the re-
action was carefully monitored by thin-layer chromatog-
raphy (TLC) to determine when to stop the reaction. In the
case of 4-bromo-2-nitrobenzoic acid (entry 8), a slight in-
crease in the amount of catalyst removed the bromide
more rapidly and minimized reduction of the nitro group.
5
6
7
8
quenching with water. Heterogeneous palladium-on-
SYNTHESIS 2010, No. 2, pp 0217–0220
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217112; Art ID: M04609SS
Georg Thieme Verlag Stuttgart · New York
©

2
18
A. Ramanathan, L. S. Jimenez
PAPER
Chlorides were readily reduced within one hour by in- Table 1 Bromides and Chlorides as Aromatic Blocking Groups
creasing the molar percentage of catalyst that was used
Entry Reactant
Product
Pd/C
Time Yield
(
entries 4 and 5). Even though TLC appeared to show that
(
mol%) (min) (%)
the reactants had been converted almost completely into
product, the isolated yields of the more volatile products
Ac
HN
Ac
(
entries 3, 6, and 9) were low because of the small scale of
HN
F
the reactions. Yields, reaction times, and mole percentag-
es of the palladium catalyst are given in Table 1 for vari-
ous benzenoid substrates.
1
0.60
0.60
40
50
quant
F
Br
Ac
R1
R1
HN
Ac
R2
HN
R2
H2, 10% Pd/C
NaHCO3, MeOH, r.t.
2
99
X
Br
X = Br or Cl
OMe
OMe
Scheme 2
3
0.60
1.5
40
60
50
22
45
30
80
93
39
75
With respect to the products listed in Table 1, N-phenyl-
acetamide has been previously monofluorinated to give
about a 2:1 ratio of the ortho and para regioisomers by
Br
OH
OH
2
1
i-Pr
treatment with acetyl hypofluorite or 1-alkyl-4-fluoro-
4
i-Pr
2
2
1
,4-diazoniabicyclo[2.2.2]octane salts (entry 1). A pal-
ladium-catalyzed methylation of N-phenylacetamide se-
lectively gave the ortho regioisomer in a 42% yield (entry
Cl
2
3
2
). Anisole has been ortho-lithiated with sec-butyllithi-
OH
O
OH
O
um and methylated with iodomethane to give a 71% yield
2
4
5
6
7
1.5
of 2-methylanisole (entry 3). A mixed zircona–titania
oxide containing 15% of phosphoric acid gave a 96%
yield of 2-hydroxyacetophenone from phenol and ethyl
Cl
2
5
acetate, along with 3% of phenyl acetate (entry 5). Di-
rect ortho-acylation of phenol with acetic acid in the pres-
ence of tin(IV)chloride under microwave conditions gave
NH2
NH2
CN
Cl
Cl
Cl
Cl
0.60
0.60
2
6
a 90% yield of 2-hydroxyacetophenone. A palladium-
catalyzed reaction with copper(II) acetate as an oxidant
gives an 80% yield of ortho-chlorinated acetanilide with a
Br
CN
2
7
high regioselectivity; hydrolysis of the amide subse-
quently gave 2-chloroaniline (entry 6).
Melting points (uncorrected) were measured on a Thomas Hoover
Br
1
13
apparatus. H and C NMR spectra were recorded on Varian VN-
MRS 300, 400, and 500 MHz spectrometers. Methanol was distilled
over calcium hydride.
CO2H
CO2H
NO2
NO2
8
9
NO2
0.82
0.60
25
35
92
52
2
-Nitrobenzoic Acid;28 Typical Procedure (Table 1, Entry 8)
Br
A dry, three-necked, 50-mL flask was charged with 4-bromo-2-ni-
trobenzoic acid (0.12 g, 0.49 mmol), 10 wt% Pd/C (4.3 mg, 0.82
NO2
mol%), NaHCO (0.133 g, 3.2 mmol), and freshly distilled anhyd
3
MeOH (1.8 mL) under N . A balloon was attached to the central
2
neck and the flask was subjected to three vacuum–fill cycles with
Br
H . The mixture was then vigorously stirred at r.t. for the indicated
2
time (Table 1). After 25 min, the soln was filtered through Celite,
and the solvent was removed in vacuo. The residue was purified by
flash chromatography [silica gel, MeOH–CH Cl (1:4)] to give light
13C NMR (75 MHz, CDCl
137.2, 138.7, 153.6, 173.7.
–DMSO-d ): d = 127.9, 134.6, 134.9,
6
3
2
2
yellow crystals; yield: 75 mg (0.45 mmol, 92%); mp 145–148 °C
(
Lit.29 146–148 °C).
N-(2-Fluorophenyl)acetamide30 (Table 1, Entry 1)
This compound was prepared from N-(4-bromo-2-fluorophe-
nyl)acetamide (94 mg) as described above for 2-nitrobenzoic acid
1
H NMR (300 MHz, CDCl –DMSO-d ): d = 7.51 (t, J = 7.7 Hz, 1
3
6
H), 7.60 (t, J = 7.4 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.77 (d, J =
3
1
to give a white powder; yield: 62 mg (quant); mp 78–80 °C (Lit.
8–79 °C).
7
.2 Hz, 1 H).
7
Synthesis 2010, No. 2, 217–220 © Thieme Stuttgart · New York

PAPER
Reductive Dehalogenation of Aryl Bromides and Chlorides
219
1
1
H NMR (500 MHz, CDCl ): d = 2.21 (s, 3 H), 6.92–7.14 (m, 3 H),
H NMR (300 MHz, CDCl ): d = 7.31 (dt, J = 7.2, 2.7 Hz, 1 H),
3
3
7
.57 (s, NH), 8.26 (t, J = 7.8 Hz, 1 H).
7.41–7.52 (m, 2 H), 7.59 (dd, J = 7.8, 0.6 Hz, 1 H).
1
3
13
C NMR (125 MHz, CDCl ): d = 24.6, 114.7 (d, J = 75.5 Hz),
C NMR (75 MHz, CDCl ): d = 113.6, 116.2, 127.4, 130.3, 134.2,
3
CF
3
1
21.9, 124.3 (d, J = 31.5 Hz), 124.6 (d, J = 15.0 Hz), 126.4 (d,
134.3, 137.1.
CF
CF
JCF = 41.0 Hz), 152.4 (d, JCF = 964.5 Hz), 168.4.
2
-Nitrotoluene39 (Table 1, Entry 9)
N-(2-Methylphenyl)acetamide30 (Table 1, Entry 2)
This compound was prepared of N-(4-bromo-2-methylphenyl)acet-
amide (230 mg) as described above for 2-nitrobenzoic acid to give
a white solid; yield: 149 mg (99%); mp 111–113 °C (Lit. 110–112
This compound was prepared from 2-bromo-6-nitrotoluene (124
mg) as described above for 2-nitrobenzoic acid, with purification by
flash chromatography (PE–EtOAc, 9:1), to give a yellow liquid;
yield: 41 mg (52%).
3
2
°
C).
1
H NMR (400 MHz, CDCl ): d = 2.59 (s, 3 H), 7.23–7.29 (m, 2 H),
3
1
H NMR (300 MHz, CDCl ): d = 2.04 (s, 3 H), 2.14 (s, 3 H), 6.98–
7.41 (dt, J = 7.6, 1.4 Hz, 1 H), 7.88 (dd, J = 8.8, 1.2 Hz, 1 H).
13
3
7
.14 (m, 3 H), 7.45 (d, J = 7.5 Hz, 1 H), 7.84 (br s, 1 H).
C NMR (100 MHz, CDCl ): d = 20.6, 124.8, 127.1, 133.0, 133.2,
3
1
3
C NMR (75 MHz, CDCl ): d = 18.1, 23.9, 124.8, 125.9, 126.6,
30.7, 131.3, 135.9, 169.5.
133.8, 149.5.
3
1
-Methylanisole33 (Table 1, Entry 3)
Acknowledgment
2
This compound was prepared from 4-bromo-2-methylanisole (272
mg) as described above for 2-nitrobenzoic acid, with purification by
flash chromatography (PE–EtOAc, 19:1), to give a pale yellow liq-
uid; yield: 49.2 mg (30%).
We thank the National Science Foundation (CHE-0316199) for
support of this research.
1
H NMR (300 MHz, CDCl ): d = 2.52 (s, 3 H), 3.86 (s, 3 H), 6.82– References
3
6
1
.93 (m, 2 H), 7.12–7.25 (m, 2 H).
(
1) (a) Sen, A. B.; Kulkarni, Y. D. J. Indian Chem. Soc. 1956,
33, 326. (b) Sakellarios, E.; Jatrides, D. Ber. Dtsch. Chem.
Ges. 1925, 58, 2286.
3
C NMR (75 MHz, CDCl ): d = 16.4, 55.5, 110.2, 120.5, 126.8,
3
1
27.0, 130.8, 159.5.
(
2) (a) Tashiro, M.; Yamato, T. J. Org. Chem. 1979, 44, 3037.
(b) Tashiro, M.; Yamato, T.; Kobayashi, K. J. Org. Chem.
1984, 49, 4724. (c) Olah, G. A.; Prakash, G. K. S.; Iyer, P.
S.; Tashiro, M.; Yamato, T. J. Org. Chem. 1987, 52, 1881.
2
-Isopropyl-5-methylphenol34 (Table 1, Entry 4)
This compound was prepared from 4-chloro-5-methyl-2-isopropyl-
phenol (200 mg) as described above for 2-nitrobenzoic acid to give
white crystals; yield: 130 mg (80%); mp 48–51 °C (Lit.35 46–47
(3) (a) For 2-alkenylanilines, see: Moutrille, C.; Zard, S. Z.
°
C).
Tetrahedron Lett. 2004, 45, 4631. (b) For anilines
1
substituted with sulfur nucleophiles at the 2-position, see:
Zhu, L.; Zhang, M. J. Org. Chem. 2004, 69, 7371. (c) For
ortho hydroxybenzylation and hydroxyalkylation of
secondary anilines, see: Sugasawa, T.; Toyoda, T.; Adachi,
M.; Sasakura, K. J. Am. Chem. Soc. 1978, 100, 4842.
H NMR (500 MHz, CDCl ): d = 1.33 (d, J = 7.0 Hz, 6 H), 2.35 (s,
3
3
7
H), 3.34 (hept, 1 H), 5.08 (s, 1 H, OH), 6.63 (s, 1 H), 6.83 (d, J =
.5 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H).
1
3
C NMR (125 MHz, CDCl ): d = 21.1, 23.0, 27.0, 116.4, 122.0,
3
1
26.6, 131.8, 136.9, 152.8.
(
d) For ortho substitution of arylsydnones, see: Lin, S. T.;
Cheo, H. S.; Chen, B. I.; Own, Z. Y. Heteroat. Chem. 1998,
, 549. (e) For ortho substitution of phenols with vinyl
1
-(2-Hydroxyphenyl)ethanone36 (Table 1, Entry 5)
9
This compound was prepared from 1-(5-chloro-2-hydroxyphe-
nyl)ethanone (164.5 mg) as described above for 2-nitrobenzoic acid
to give a light yellow liquid; yield: 122.5 mg (93%)
1
ethers, see: Copeland, C. M.; Ghosh, J.; McAdam, D. P.;
Skelton, B. W.; Stick, R. V.; White, A. H. Aust. J. Chem.
1988, 41, 69.
H NMR (400 MHz, CDCl ): d = 2.59 (s, 3 H), 6.87 (dt, J = 7.6, 1.0
(4) Pinder, A. R. Synthesis 1980, 425.
3
Hz, 1 H), 6.94 (dd, J = 8.4, 1.2 Hz, 1 H), 7.43 (dt, J = 7.8, 1.4 Hz, 1
H), 7.70 (dd, J = 8.0, 1.6 Hz, 1 H).
(5) (a) Choi, H. Y.; Chi, D. Y. J. Am. Chem. Soc. 2001, 123,
9202. (b) Adimurthy, S.; Ramachandraiah, G.; Bedekar, A.
V. Tetrahedron Lett. 2003, 44, 6391. (c) Adimurthy, S.;
Ramachandraiah, G. Tetrahedron Lett. 2004, 45, 5251.
1
3
C NMR (100 MHz, CDCl ): d = 26.8, 118.6, 119.2, 119.9, 131.0,
3
1
36.7, 162.6, 204.8.
(6) Tashiro, M.; Watanabe, H.; Tsuge, O. Org. Prep. Proced.
Int. 1975, 7, 43.
2
-Chloroaniline37 (Table 1, Entry 6)
(
(
7) Effenberger, F. Angew. Chem. Int. Ed. 2002, 41, 1699.
8) (a) van Zijl, P. C. M.; Jenneskens, L. W.; Bastiaan, E. W.;
MacLean, C.; de Wolff, W. H.; Bickelhaupt, F. J. Am. Chem.
Soc. 1986, 108, 1415. (b) Jensen, J.; Tejler, J.; Waernmark,
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This compound was prepared from 4-bromo-2-chloroaniline (124
mg) as described above for 2-nitrobenzoic acid, with purification by
flash chromatography (PE–EtOAc, 9:1), to give a yellow liquid;
yield: 30 mg (39%).
1
H NMR (500 MHz, CDCl ): d = 4.01 (s, NH , 2 H), 6.71 (dt, J =
3
2
7
.8, 1.5 Hz, 1 H), 6.77 (dd, J = 8, 1.3 Hz, 1 H), 7.08 (dt, J = 7.5, 1.3
(
Hz, 1 H), 7.26 (dd, J = 8.0, 1.5 Hz, 1 H).
1
3
C NMR (125 MHz, CDCl ): d = 115.9, 119.0, 119.3, 127.6, 129.4,
3
(
(
10) Tashiro, M.; Fukata, G. J. Org. Chem. 1977, 42, 835.
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42.9.
-Chlorobenzonitrile38 (Table 1, Entry 7)
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0, 169. (b) Takahashi, M.; Konishi, H.; Iida, S.; Nakamura,
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2
3
This compound was prepared from 4-bromo-2-chlorobenzonitrile
169 mg) as described above for 2-nitrobenzoic acid, with purifica-
tion by flash chromatography (PE–EtOAc, 9:1), to give a pale yel-
(
5
3
8
low solid; yield: 80.5 mg (75%); mp 44–46 °C (Lit. 44–45 °C).
Synthesis 2010, No. 2, 217–220 © Thieme Stuttgart · New York

2
20
A. Ramanathan, L. S. Jimenez
PAPER
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Synthesis 2010, No. 2, 217–220 © Thieme Stuttgart · New York