Efficient microwave-assisted Pd-catalyzed hydroxylation of aryl chlorides in the presence of carbonate

Article abstract of DOI:10.1021/ol301523q

An efficient microwave-assisted, palladium-catalyzed hydroxylation of aryl chlorides in the presence of a weak base carbonate was developed, which rapidly converts aryl and heteroaryl chlorides to phenols, and can be used when the aryl chloride is functionalized with a ketone, aldehyde, ester, nitrile, or amide.

Full text of DOI:10.1021/ol301523q

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3688–3691
Efficient Microwave-Assisted
Pd-Catalyzed Hydroxylation of Aryl
Chlorides in the Presence of Carbonate
Chao-Wu Yu,† Grace S. Chen,‡ Chen-Wei Huang,† and Ji-Wang Chern*,†,§
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 10051,
Taiwan, Republic of China, Department of Applied Chemistry, Providence University,
Taichung 43301, Taiwan, Republic of China, and Department of Life Science, College of
Life Science, National Taiwan University, Taipei 10617, Taiwan, Republic of China
jwchern@ntu.edu.tw
Received June 3, 2012
ABSTRACT
An efficient microwave-assisted, palladium-catalyzed hydroxylation of aryl chlorides in the presence of a weak base carbonate was developed,
which rapidly converts aryl and heteroaryl chlorides to phenols, and can be used when the aryl chloride is functionalized with a ketone, aldehyde,
ester, nitrile, or amide.
Phenols are important moieties of various pharmaceu-
ticals, polymers, and natural products and serve as useful
intermediates.1 Their preparations by nonoxidative meth-
ods include nucleophilic substitution of activated aryl
halides, copper-catalyzed conversion of diazoarenes, and
addition of benzyne.2 These methods are hampered by
harsh conditions and limited availablility of starting ma-
terials. Copper-catalyzed hydroxylation of aryl halides
with various ligands was reported recently,3 as was the
transformation of aryl iodides and bromides into phenols
under aqueous conditions using FeCl3 as the catalyst.4
However, a much longer reaction time was required for
copper- or iron-catalyzed reactions when compared to
palladium. Additionally, palladium is the most efficient
catalyst for the synthesis of phenols from aryl halides as
shown by the palladium-catalyzed hydroxylation of aryl
halides with bulky dialkyl or trialkylphosphine ligands,5
even though the reactions required several hours to 2 days.
However, none of the aforementioned studies5 used an
amide-derivatized aryl halide, and only one example of a
substrate containing an ethyl ester has been reported,
† School of Pharmacy, National Taiwan University.
‡ Department of Applied Chemistry, Providence University.
§ Department of Life Science, National Taiwan University.
which used K3PO4 H2O as a base affording a phenol
3
(1) Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New
York, 1996.
product in moderate yield. To shorten the reaction time,
microwave (μW) irradiation has been widely applied to the
(2) (a) Rogers, J. F.; Green, D. M. Tetrahedron Lett. 2002, 43, 3585.
(b) Cohen, T.; Dietz, A. G.; Miser, J. R. J. Org. Chem. 1977, 42, 2053. (c)
Agnello, L.; Williams, W. Ind. Eng. Chem. 1960, 52, 894.
(3) (a) Tlili, A.; Xia, N.; Monnier, F.; Taillefer, M. Angew. Chem., Int.
Ed. 2009, 48, 8725. (b) Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan,
J.; You, J. Angew. Chem., Int. Ed. 2009, 48, 8729. (c) Paul, R.; Ali, M. A.;
Punniyamurthy, T. Synthesis 2010, 2010, 4268. (d) Maurer, S.; Liu, W.;
Zhang, X.; Jiang, Y.; Ma, D. Synlett 2010, 2010, 976. (e) Yang, D.; Fu,
H. Chem.;Eur. J. 2010, 16, 2366. (f) Jing, L.; Wei, J.; Zhou, L.; Huang,
Z.; Li, Z.; Zhou, X. Chem. Commun. 2010, 46, 4767. (g) Thakur, K. G.;
Sekar, G. Chem. Commun. 2011, 47, 6692. (h) Yang, K.; Li, Z.; Wang, Z.;
Yao, Z.; Jiang, S. Org. Lett. 2011, 13, 4340. (i) Xu, H.-J.; Liang, Y.-F.;
Cai, Z.-Y.; Qi, H.-X.; Yang, C.-Y.; Feng, Y.-S. J. Org. Chem. 2011, 76,
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1463.
(4) Ren, Y.; Cheng, L.; Tian, X.; Zhao, S.; Wang, J.; Hou, C.
Tetrahedron Lett. 2010, 51, 43.
(5) (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 10694. (b) Chen, G.; Chan, A. S. C.;
Kwong, F. Y. Tetrahedron Lett. 2007, 48, 473. (c) Gallon, B. J.; Kojima,
R. W.; Kaner, R. B.; Diaconescu, P. L. Angew. Chem., Int. Ed. 2007, 46,
€
7251. (d) Schulz, T.; Torborg, C.; Schaffner, B.; Huang, J.; Zapf, A.;
€
Kadyrov, R.; Borner, A.; Beller, M. Angew. Chem., Int. Ed. 2009, 48,
918. (e) Sergeev, A. G.; Schulz, T.; Torborg, C.; Spannenberg, A.;
Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 7595. (f)
Dumrath, A.; Wu, X.-F.; Neumann, H.; Spannenberg, A.; Jackstell, R.;
Beller, M. Angew. Chem., Int. Ed. 2010, 49, 8988.
r
10.1021/ol301523q
Published on Web 07/03/2012
2012 American Chemical Society

Table 1. Optimization of Pd-Catalyzed Hydroxylation of 6-Chloroquinolinea
entry
solvent
concn (M)
temp (°C)
base
K2CO3
heating mode
yield (%)b
1
DMF/H2O (1:1)
DMF/H2O (3:1)
DMF/H2O (9:1)
DMF/H2O (24:1)
DMF/H2O (9:1)
DMF/H2O (9:1)
DMF/H2O (9:1)
DMA/H2O (9:1)
DMF/H2O (9:1)
DMF/H2O (9:1)
dioxane/H2O (9:1)
MeCN/H2O (9:1)
DMF/H2O (9:1)
DMF/H2O (9:1)
DMF
0.2
0.2
0.2
0.2
0.4
0.4
0.4
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
125
125
125
125
125
125
100
125
115
100
100
100
115
100
115
100
125
120
CVc
CV
CV
CV
CV
CV
CV
CV
37
2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
68
3
87
4
81
5
85 (82)d
79
6
7
81
8
89
e
9
OV
99
10
11
12
13
14
15
16
17
18
OV
51
OV
tracef
trace
91g
trace
66
OV
Oil bath
OV
K3PO4 H2O
OV
3
DMF
Na2CO3 H2O
OV
trace
trace
36
3
DMF
Na2CO3 H2O
OV
3
H2O
K2CO3
CV
a 6-Chloroquinoline (1.0 mmol), 2 mol % Herrmann’s palladacycle, 8 mol % t-BuXPhos, base (3.0 mmol), solvent (2.5 mL for 0.4 M and 5 mL for 0.2
M), Ar, μW, 20 min. b Determined by 1H NMR of crude product using dibromomethane as an internal standard. c CV: Close vessel. d Isolated yield. e OV:
Open vessel. f Monitored by TLC. g 11 h.
organic synthesis. Leadbeater et al.6 reported that the
copper-catalyzed conversion of aryl halides to phenols
between 180 and 300 °C proceeded more rapidly with
μW irradiation.
Table 2. Pd-Catalyzed Hydroxylation of 6-Chloroquinoline
with Different Pd-Catalysts and Ligandsa
With the ultimate goal of shortening the reaction time
and increasing the types of substrates that can be used, we
report herein that the use of a weak base and μW is suitable
for the Pd-catalyzed hydroxylation of 6-chloroquinoline.
Moreover, although aryl chlorides are less expensive, they
are less reactive substrates5b than aryl iodides and bro-
mides. We report an efficient process for hydroxylation of
aryl chlorides catalyzed by palladium using dialkylpho-
sphine ligands in DMF/H2O (9:1) in the presence of
potassium or cesium carbonate under μW irradiation.
During our study of quinazoline derivatives,7 6-chlor-
oquinoline served as a model reactant when optimizing
hydroxylation conditions. For the present study, initially
the catalyst Herrmann’s palladacycle was used in a closed
microwave vessel, and the solvent and base were varied.
The mixed solvent DMF/H2O (9:1) provided a satisfactory
yield (87%; Table 1, entry 3). Neither an increased 6-chloro-
quinoline concentration nor the use of Cs2CO3 improved
the yield (Table 1, entries 5 and 6). A comparable yield was
obtained with DMA/H2O as the solvent (89%; Table 1,
entry 8). To avoid carbonylation or other possible side
entry
1
cat. (mol %)
yieldb
99%
Herrmann’s palladacycle (2 mol %)/
L1 (8 mol %)
2
3
4
5
6
Pd2(dba)3 (2 mol %)/L1 (8 mol %)
Pd(OAc)2 (2 mol %)/L1 (8 mol %)
Pd(OAc)2 (2 mol %)/L2 (8 mol %)
Pd(OAc)2 (2 mol %)/L3 (8 mol %)
Herrmann’s palladacycle (2 mol %)
82%
94%
27%
tracec
no
reaction
a 6-Chloroquinoline (1.0 mmol), K2CO3 (3.0 mmol), solvent (5 mL),
Ar, μW, 115 °C, 20 min. b Determined by 1H NMR of crude product
using dibromomethane as an internal standard. c Monitored by TLC.
reactions induced by high pressure,8 some of the reactions
were carried out in open vessels, which, interestingly,
improved the yield when the reaction was run at a lower
(6) (a) Kormos, C. M.; Leadbeater, N. E. Tetrahedron 2006, 62, 4728.
(b) Mehmood, A.; Leadbeater, N. E. Catal. Commun. 2010, 12, 64.
(7) Deore, R. R.; Chen, G. S.; Chen, C.-S.; Chang, P.-T.; Chuang,
M.-H.; Chern, T.-R.; Wang, H.-C.; Chern, J.-W. Curr. Med. Chem.
2012, 19, 603–614.
(8) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6232.
Org. Lett., Vol. 14, No. 14, 2012
3689

Table 3. Pd-Catalyzed Synthesis of Phenols from Aryl Chlor-
idesa
Table 4. Pd-Catalyzed Synthesis of Phenols from Heteroaryl
Chloridesa
a ArCl (1.0 mmol), palladacycle (2 mol %), L1 (8 mol %), K2CO3 (3.0
equiv), DMF/H2O (9:1, 5 mL), μW, 115 °C, 30 min. b Isolated yield.
c With Cs2CO3 (3 equiv) at 150 °C. d With Cs2CO3 at 130 °C.
Different palladium sources and ligands were also
screened with the use of K2CO3 (Table 2). In addition to
Herrmann’s palladacycle, Pd2(dba)3 and Pd(OAc)2 pro-
vided satisfactory yields in combination with L1 (entries 2
and 3). Additionally, a ratio of 1:2 or 1:4 of palladium
to ligand gave comparable results (entries 1À3). The
catalytic activity decreased substantially with the use of
dicyclohexylphosphine (L2, entry 4) or [(t-Bu)3PH]BF4 (L3,
entry 5). The reaction did not occur in the absence of ligand
(entry 6).
a ArCl (1.0 mmol), palladacycle (2 mol %), L1 (8 mol %), K2CO3 (3.0
equiv), DMF/H2O (9:1, 5 mL), μW, 115 °C, 30 min. b Isolated yield.
c Yield in parentheses was determined by 1H NMR of crude product
using dibromomethane as an internal standard. d Volatile compound.
e With Cs2CO3 (3 equiv) at 150 °C. f With K3PO4 at 130 °C.
Having established reaction conditions that produced a
substantial yield of 6-hydroxyquinoline, different electron-
poor and electron-rich aryl chlorides were used as sub-
strates to explore the scope of the reaction (Table 3).
Aldehyde, nitrile, methyl ketone, and amide were toler-
ated under the reaction conditions (entries 1À4). To our
knowledge, hydroxylation of an aryl chloride bearing a
free amide group has not been reported. Additionally,
the vulnerable methyl ester derivative gave a high
yield without hydrolysis (entry 5). Aryl chlorides con-
taining a substituent at the ortho position reacted
smoothly (entries 6 and 7). The deactivated aryl chlo-
rides gave lower yields (entries 8, 9, 11, and 12), and
therefore the reaction required a higher temperature.
In general, Cs2CO3 provided better results than did
K2CO3. For example, Cs2CO3 was needed for the deac-
tivated para nitrogen-substituted substrates (entries 8
and 9) since the substrates could not be completely
converted by K2CO3 within 30 min. K3PO4 also pro-
vided a moderate yield with 4-chloroanisole as the
substrate (entry 11).
temperatureof 115 °C (99%;Table 1, entry 9). However, at
100 °C with DMF/H2O, dioxane/H2O, or MeCN/H2O as
the solvent, the yield dramatically decreased (Table 1,
entries 10À12). Conventional heating at 115 °C also pro-
duced a high yield, but a longer reaction time (11 h) was
needed (Table 1, entry 13) when compared to μW irradia-
tion (20 min) under the same reaction conditions (Table 1,
entriy 9). A significant amount of Pd-black was formed
with the use of KOH, and the catalytic efficiency was
decreased with the use of L1 and KOH because the
palladium catalyst was not stable (entry 14).5a A decreased
yield might also have resulted from DMF instability in the
presence of KOH.9 Lower yields were obtained when the
hydrate of a base was used rather than the cosolvent
H2O (DMF/H2O (9:1); Table 1, entries 15À17). With the
K2CO3/H2O system, the yield was only 36% (Table 1,
entry 18).
(9) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 6th ed.; Butterworth-Heinemann: Oxford, 2009; p 130.
3690
Org. Lett., Vol. 14, No. 14, 2012

Microwave irradiation/Pd catalysis was also applied
to heteroaryl chlorides (Table 4). The chloro-substituted
quinoline and quinoxaline derivatives were converted to
the corresponding hydroxy derivatives in high yield (entries
1À3). Again, introduction of a para electron-donating
group gave lower yields (entries 4À6) as for aryl chlorides
(entries 8, 9, 11, and 12, Table 3). 2-Methyl benzothiazole
stayed intact during the hydroxylation (entry 6).
In summary, an efficient protocol for palladium-
catalyzed hydroxylation of aryl and heteroaryl chlorides
was developed. To our knowledge, carbonate has not
been reported as an efficient base for either copper- or
palladium-catalyzed hydroxylation. The present catalytic
system does not substantially hydrolyze potentially vulner-
able functional groups and can be used with either con-
ventional heating or microwave irradiation.
Acknowledgment. Financial support was provided by
the National Science Council (99-2323-B-002-009), Tai-
wan, ROC.
Supporting Information Available. Experimental pro-
cedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.
org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3691