Directed palladium-catalyzed oxidative C-H arylation of (hetero)arenes with arylboronic acids by using TEMPO

Article abstract of DOI:10.1055/s-0028-1083546

Oxidative coupling of three different arenes and a thiophene derivative with various arylboronic acids with Pd(OAc)₂ and the commercially available 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an oxidant are reported. A 2-pyridyl gro

Full text of DOI:10.1055/s-0028-1083546

LETTER
2841
Directed Palladium-Catalyzed Oxidative C–H Arylation of (Hetero)arenes
with Arylboronic Acids by Using TEMPO
P
alladium-Cat
y
alyze
d
O
xida
l
tive
C
v
–H
A
rylation
i
of (H
e
a
tero)arenes Kirchberg, Thomas Vogler, Armido Studer*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8336523; E-mail: studer@uni-muenster.de
Received 25 June 2008
the fact that Pd catalysts are cheaper than Rh catalysts. In
the present letter we disclose our first results on Pd-cata-
lyzed aryl–aryl bond-forming reactions with arylboronic
acids as coupling partners in combination with TEMPO as
Abstract: Oxidative coupling of three different arenes and a
thiophene derivative with various arylboronic acids with Pd(OAc)2
and the commercially available 2,2,6,6-tetramethylpiperidine-N-
oxyl radical (TEMPO) as an oxidant are reported. A 2-pyridyl group
on the substrates serves as ortho-directing group to mediate the an environmentally benign oxidant. To the best of our
C–H arylation. Mechanistic studies are provided.
knowledge, TEMPO has not been used as an external ox-
idant in Pd-catalyzed direct C–H arylations of arenes with
Key words: biaryls, boronic acids, C–H arylation, nitroxides, pal-
ladium
aryl- or alkylboronic acids.14
Initial studies were performed with arene 1, bearing the
ortho-directing 2-pyridyl group,15 and phenylboronic acid
(4 equiv) by using various Pd catalysts (10 mol%) in the
presence of excess TEMPO (4 equiv) under different con-
ditions to give 2a (Table 1). As a side product the bisar-
ylated arene 3a was identified in all reactions performed.
Biaryls are an important class of compounds which are of-
ten used as ligands in asymmetric synthesis.1 Moreover,
they occur in various natural products2 and are also valu-
able building blocks for the construction of organic mate-
rials.3,4 Biaryls have been predominantly prepared by
metal-catalyzed cross-coupling reactions of aryl halides
and aryl metal compounds.1 More recently, many research
groups have focused on the direct arylation of arenes and
heteroarenes without preactivation of one5 or two6 of the
coupling partners. In most of these reports, Pd catalysts
have been used for arene activation, but various other met-
als have been successfully employed as well.5 Most of the
Pd-catalyzed processes use aryl halides as the activated
coupling partner for C–H arylation.5 Aryl- and alkylbo-
ronic acids7 have also been applied as coupling partners
by Murai,8 Sames,9 Shi,10 and Yu.11 We have recently de-
veloped a Rh-catalyzed directed C–H arylation of various
arenes with boronic acids by using TEMPO (2,2,6,6-tet-
ramethylpiperidine-N-oxyl radical) as an oxidant
(Scheme 1).12,13
The influence of the solvent with Pd(OAc)2 as a catalyst
was investigated first. Reactions were conducted at 50 °C
for five days. The C–H arylation in propionic acid was
slow and 2a was isolated in only 20% yield along with
traces of 3a (Table 1, entry 1). Pleasingly, the yield could
be improved upon switching to acetic acid as a solvent un-
der otherwise identical conditions (57%, entry 2). No base
was required for this reaction. The C–H arylation in
DMSO and DMF were low yielding (entries 3 and 4). An
acceptable result was achieved in dimethylacetamide
(DMA, entry 5). After having identified acetic acid as best
solvent we varied the catalyst; (C3H5PdCl)2 and Pd(acac)2
showed lower activities as compared to Pd(OAc)2 (entries
6 and 7). Phosphine and sulfoxide ligands turned out to be
detrimental to the C–H arylation (entries 8 and 9). The
more electrophilic Pd(CF3CO2)2 showed a moderate ac-
tivity (entry 10). Importantly, upon using KF (4 equiv) as
an additive with Pd(OAc)2 as a catalyst, reaction time
could be decreased without affecting the yield to a large
extent (entry 11). Decreasing or increasing the reaction
temperature did not improve the yield (entries 12–15). We
also tried to run the reaction by using a substoichiometric
amount of TEMPO (10 mol%) with oxygen (9.8692 × 10–6
Pa) as a terminal oxidant.12 However, only traces of the
products were formed.
This process is useful since TEMPO and many arylboron-
ic acids are commercially available. Based on these re-
sults we initiated a program on the direct C–H arylation of
arenes with arylboronic acids by using Pd catalysts and
TEMPO as an external oxidant. This study was driven by
[RhCl(C2H4)2]2 (5 mol%)
[4-F3CC6H4]3P (20 mol%)
ArB(OH)2 (4 equiv)
N
N
Ar
H
Under the optimized conditions other arylboronic acids
were tested in the arylation of 1.16 As expected, the tolyl
derivative 4-MeC6H4B(OH)2 provided a similar result
(Table 1, entry 17). The reaction with 4-FC6H4B(OH)2
provided selectively the monoarylated product 2b in 55%
yield (entry 16). However, heteroarylboronic acids such
as 2-thienyl and 2-furylboronic acid did not undergo di-
rect C–H-arylation under the optimized conditions.
TEMPO (4 equiv)
dioxane–t-BuOH (10:1)
130 °C
49–99%
Scheme 1 Rhodium-catalyzed directed C–H arylation
SYNLETT 2008, No. 18, pp 2841–2845
1
4
.1
1
.2
0
0
8
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083546; Art ID: G22608ST
© Georg Thieme Verlag Stuttgart · New York

2842
S. Kirchberg et al.
LETTER
arylations.12 As compared to the transformations of 1 or 4,
we found that reaction with 6 is far faster, and product 7a
was isolated in 74% yield after 24 hours’ reaction time
(Scheme 3). Increasing the reaction time did not further
improve the yield. With substrate 6 efficient arylation
could also be achieved by using 2 equivalents of
PhB(OH)2 (64%) or by using 2 equivalents of TEMPO
(57%).16
Table 1 Palladium-Catalyzed Directed C–H Arylation under Dif-
ferent Conditions
Pd salt (10 mol%)
TEMPO (4 equiv)
N
N
N
ArB(OH)2 (4 equiv)
+
Ar
Ar
Ar
solvent, additive
1
2a Ar = Ph
2b Ar = 4–FC6H4
2c Ar = Tol
3a Ar = Ph
3b Ar = 4–FC6H4
3c Ar = Tol
Pd(OAc)2 (10 mol%)
TEMPO (4 equiv)
ArB(OH)2 (4 equiv)
N
N
Entry Pd catalyst
Solvent Temp Time Yield (%)a
(°C) (d) 2a/3a
EtO
Ar
EtO
KF (4 equiv), 50 °C
AcOH, 24 h
1
2
Pd(OAc)2
EtCO2H
AcOH
DMSO
DMF
50
50
50
50
50
50
50
50
50
50
50
30
40
70
100
50
50
5
5
5
7
7
5
6
6
7
6
3
5
5
6
6
3
3
22/1
Pd(OAc)2
57/7
6
7a Ar = Ph 74%
7b Ar = Tol 54%
7c Ar = PMP 24%
3
Pd(OAc)2
25/1
7d Ar = 4–FC6H4 41%
7e Ar = 3–ClC6H4 65%
7f Ar = 4–vinylC6H4 23%
4
Pd(OAc)2
13/1
5
Pd(OAc)2
DMA
49/4
Scheme 3 Palladium-catalyzed directed C–H arylation of 6
6
(C3H5PdCl)2
Pd(acac)2
AcOH
AcOH
AcOH
25/5
Good yields in the arylation of 6 were obtained with
4-MeC6H4B(OH)2 (→ 7b, 54%) and 3-ClC6H4B(OH)2 (→ 7e,
65%). Electronic effects at the boronic acid moiety
strongly influenced the reaction outcome. The electron-
poor para-fluoro boronic acid [4-FC6H4B(OH)2] deliv-
ered 7d in 41% yield, whereas only a moderate yield
was obtained with the electron-rich 4-MeOC6H4B(OH)2
(→ 7c, 24%). The C–H arylation with 4-vinyl-
C6H4B(OH)2 occurred in a low yield (→ 7f, 23%).
We suggest the following mechanism for the Pd-catalyzed
direct C–H arylation (Scheme 4). In acetic acid as solvent
the active catalyst is supposed to be Pd(OAc)2 which un-
dergoes pyridyl-directed C–H arylation to give A (see dis-
cussion below). Transmetalation with an arylboronic acid
leads to B which subsequently undergoes reductive
elimination to afford product C and a Pd(0) species. The
Pd(0) species is then oxidized with 2 equivalents of
TEMPO to give after reaction with acetic acid Pd(OAc)2
and TEMPOH.
7
35/3
8
Pd(PPh3)2(OAc)2
20/3
9
(PhSOCH2)2Pd(OAc)2 AcOH
37/3
10
Pd(CF3CO2)2
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
46/7
11b Pd(OAc)2
52/9
12
13
14
15
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
33/2
37/5
38/4
28/1
16b Pd(OAc)2
17b Pd(OAc)2
55 (2b)/–(3b)
49 (2c)/8 (3c)
a Isolated yield.
b KF (4 equiv) was added.
The C–H activation may either occur via electrophilic ar-
omatic substitution5 or via a concerted proton transfer–
metalation pathway.17,18 For substrate 1 we decided to
study the primary kinetic isotope effect and also the inter-
molecular kinetic isotope effect. Thus, compound D-1
was reacted under optimized conditions with PhB(OH)2
and TEMPO to give 2a and the deuterated compound
D-2a in a ratio of 1:4.5, as determined by mass spectrom-
etry (Scheme 5).19,20 This result indicates that the reaction
of 1 with PhB(OH)2 seems to occur via a concerted proton
transfer–metalation pathway mechanism.17,18 Moreover,
we studied the intermolecular kinetic isotope effect. To
this end, 1 and D2-121 (ratio 1:0.88) were reacted with
PhB(OH)2 for 4 hours (low conversion). An isotope effect
of 1.43 was calculated based on the ratio of unreacted
starting material (MS analysis). The smaller intermolecu-
lar kinetic isotope effect indicated that complexation of
Pd(OAc)2 (10 mol%)
N
N
TEMPO (4 equiv)
ArB(OH)2 (4 equiv)
Ar
KF (4 equiv), 50 °C
AcOH, 3 d
S
S
4
5a Ar = Ph 46%
5b Ar = 3–ClC6H4 46%
5c Ar = Tol 45%
Scheme 2 Palladium-catalyzed directed C–H arylation of 4
The 2-pyridyl-substituted thiophene derivative 4 could
also be arylated under the same conditions (Scheme 2).16
Products 5a–c were obtained in 45–46% yield.
We continued our studies with arene 6, which was identi-
fied as an efficient substrate for our Rh-catalyzed C–H
Synlett 2008, No. 18, 2841–2845 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Oxidative C–H Arylation of (Hetero)arenes
2843
We also looked at the intermolecular kinetic isotope effect
for the more nucleophilic substrate 6. To this end, a mix-
ture of 6 and D-6 (0.87:1) was reacted under the optimized
conditions with PhB(OH)2 for 4 hours. The MS analysis
of the remaining starting material revealed an intermolec-
ular kinetic isotope effect of 1.21. Since 6 is more reactive
than 1 we assume that complexation of 6 is also irrevers-
ible under the applied conditions. Hence, the experimen-
tally determined intermolecular kinetic isotope effect
does not allow any conclusion on the mechanism of the
C–H activation step for that substrate.
N
N
Pd(OAc)2
OH
AcOH
2 TEMPO
2 AcOH
AcO
Pd
2
In conclusion, we presented Pd(OAc)2-catalyzed C–H
arylations of four different arenes with readily available
arylboronic acids as coupling partners. Commercially
available environmentally benign TEMPO was used as a
terminal oxidant. The pyridyl group served as directing
group to mediate the C–H arylation.
Pd(0)Ln
N
A
Ar
Ar
PdLn
ArB(OH)2
N
Acknowledgment
N
(AcO)B(OH)2
C
We thank the Fonds der Chemischen Industrie (stipend to T.V.) and
Novartis Pharma AG (Young Investigator Award to A.S.) for finan-
cial support. Evonik Degussa GmbH is acknowledged for donation
of chemicals.
B
Scheme 4 Suggested mechanism for Pd-directed C–H arylation
with TEMPO as external oxidant
References and Notes
(1) (a) Pu, L. Chem. Rev. 1998, 98, 2405. (b) Hassan, J.;
Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(2) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser,
M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005,
44, 5384.
Pd(OAc)2 (10 mol%)
N
N
N
TEMPO (4 equiv)
PhB(OH)2 (4 equiv)
D
Ph
D
H
Ph
+
KF (4 equiv), 50 °C
AcOH, 3 d
D-1
D-2a
(D-2a/2a = 4.5:1)
2a
(3) Kraft, A.; Grimsdale, A. C.; Holmes, A. B. Angew. Chem.
Int. Ed. 1998, 37, 402.
(4) Roncali, J. Chem. Rev. 1992, 92, 711.
(5) Recent reviews: (a) Yu, J.-Q.; Giri, R.; Chen, X. Org.
Biomol. Chem. 2006, 4, 4041. (b) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35.
(c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (e) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007,
36, 1173.
Pd(OAc)2 (10 mol%)
TEMPO (4 equiv)
PhB(OH)2 (4 equiv)
N
N
+
D
D
D-2a + 2a
KF (4 equiv), 50 °C
AcOH, 4 h
1
D2-1
(6) (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
11904. (b) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 12072. (c) Dwight, T. A.; Rue, N. R.;
Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9,
3137. (d) Rong, Y.; Li, R.; Lu, W. Organometallics 2007,
26, 4376. (e) Xia, J.-B.; You, S.-L. Organometallics 2007,
26, 4869. (f) Stuart, D. R.; Fagnou, K. Science 2007, 316,
1172. (g) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew.
Chem. Int. Ed. 2008, 47, 1115.
at 0 h: D2-1/1 = 0.88:1
after 4 h: D2-1/1 = 1.26:1
kH/kD = 1.43
Pd(OAc)2 (10 mol%)
TEMPO (4 equiv)
ArB(OH)2 (4 equiv)
N
N
N
EtO
EtO
D
EtO
Ph
+
KF (4 equiv), 50 °C
AcOH, 4 h
(7) For oxidative Heck coupling with arylboronic acids, see:
(a) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083.
(b) Ruan, J.; Li, X.; Saidi, O.; Xiao, J. J. Am. Chem. Soc.
2008, 130, 2424; and references cited therein.
(8) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S.
J. Am. Chem. Soc. 2003, 125, 1698. (b) Kakiuchi, F.; Usui,
M.; Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004,
126, 2706.
6
D-6
7a
at 0 h: D-6/6 = 0.87:1
after 4 h: D-6/6 = 1.05:1
kH/kD = 1.21
Scheme 5 Kinetic isotope effect for the reaction with D-1, 1/D2-1
and 6/D-6
(9) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc.
2006, 128, 14220.
(10) (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin,
the Pd catalyst with the pyridyl group is to a large extend
irreversible (ligand exchange slower than C–H activa-
tion).
Synlett 2008, No. 18, 2841–2845 © Thieme Stuttgart · New York

2844
S. Kirchberg et al.
LETTER
C.; Wang, Y. Angew. Chem. Int. Ed. 2007, 46, 5554.
(b) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1473.
ethane were heated in a sealed reaction tube at 130 °C for 24
h.23 Dichloromethane (10 mL) and Na2S (aq sat., 10 mL)
were added. The mixture was filtered over Celite and the
filtrate was washed with brine (2 × 10 mL). The combined
organic layers were dried over MgSO4 and the volatiles were
removed under reduced pressure. The residue was purified
by flash chromatography (pentane–MTBE, 20:1).
(11) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 12634. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang,
D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. (c) Wang, D.-H.; Wasa, M.;
Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(12) Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129.
(13) Vogler, T.; Studer, A. Synthesis 2008, 1979.
(14) Shi and Yu used Cu(II) salts as stoichiometric oxidants, see
refs. 10 and 11.
(15) (a) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439.
(b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.;
Inoue, Y. Org. Lett. 2001, 3, 2579. (c) Kalyani, D.; Deprez,
N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 7330. (d) Shabashov, D.; Daugulis, O. Org. Lett. 2005,
7, 3657. (e) Ackermann, L.; Althammer, A.; Born, R.
Angew. Chem. Int. Ed. 2006, 45, 2619. (f) Ackermann, L.;
Born, R.; Álvarez-Bercedo, P. Angew. Chem. Int. Ed. 2007,
46, 6364.
2-(2-Bromo-6-deuterophenyl)pyridine
To a solution of 2-(2,6-dibromophenyl)pyridine (313 mg,
1.0 mmol) in THF (20 mL) at –78 °C was added dropwise
n-BuLi (1.68 M solution in hexanes, 0.60 mL, 1.00 mmol).23
The mixture was stirred for 30 min. Then, D2O (2.0 mL) was
added and stirring was continued for additional 30 min. The
mixture was allowed to warm to r.t., and EtOAc (10 mL) and
brine (20 mL) were added. The mixture was extracted with
EtOAc (3 × 20 mL), dried over MgSO4, and the volatiles
were removed under reduced pressure. The residue was
purified by flash chromatography (pentane–MTBE, 50:1)
and the product was obtained as a yellow oil (0.181 g, 0.68
mmol, 77%). The product was used without any further
characterization.
(16) General Experimental Procedure
2-(2,6-Dideuterophenyl)pyridine (D2-1)
The corresponding boronic acid (1.00 mmol), TEMPO (156
mg, 1.00 mmol), KF (58 mg, 1.0 mmol), Pd(OAc)2 (5.6 mg,
25 mmol), the pyridine derivative (0.25 mmol), and AcOH (1
mL) were stirred in a sealed tube at 50 °C for 24 h or 72 h,
respectively. Water (3 mL) and brine (1 mL) were added and
the mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried over MgSO4 and the
volatiles were removed under reduced pressure. The residue
was purified by flash chromatography.
To a solution of 2-(2-bromo-6-deuterophenyl)pyridine (160
mg, 0.68 mmol) in THF (10 mL) at –78 °C was added
dropwise n-BuLi (1.68 M solution in hexanes, 0.4 mL, 0.68
mmol).23 The mixture was stirred for 30 min. Then, D2O (1.0
mL) was added and stirring was continued for additional 30
min. The mixture was allowed to warm to r.t., and EtOAc
(5 mL) and brine (10 mL) were added. The mixture was
extracted with EtOAc (3 × 10 mL), dried over MgSO4, and
the volatiles were removed under reduced pressure. The
residue was purified by flash chromatography (pentane–
MTBE, 50:1) and the product was obtained as a colorless oil
(0.104 g, 0.66 mmol, 97%, 88 atom% D). 1H NMR (300
MHz, CDCl3): d = 8.68 (d, J = 4.78 Hz, 1 H, aryl-H), 7.69
(d, J = 3.52 Hz, 2 H, aryl-H), 7.42 (m, 3 H, aryl-H), 7.19 (m,
1 H, aryl-H). 13C NMR (75 MHz, CDCl3): d = 157.4 (C),
149.7 (C-H), 139.3 (C), 136.7 (CH), 129.0 (CH), 128.7
(CH), 126.6 (J = 23 Hz, CD), 122.1 (CH), 120.5 (CH). ESI-
HRMS: m/z calcd for C11H7D2N [M + H]+: 157.0933; found:
157.0939.
(17) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (b) Garcia-Cuadrado, D.; de Mendoza, P.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc.
2007, 129, 6880.
(18) Gómez, M.; Granell, J.; Martinez, M. J. Chem. Soc., Dalton
Trans. 1998, 37.
(19) Determination of the Kinetic Isotope Effects
According to the general experimental procedure with 2-(2-
deuterophenyl)pyridine (D-1, 39 mg, 0.25 mmol) and
phenylboronic acid (122 mg, 1.00 mmol) for 72 h. Flash
chromatography (pentane–EtOAc, 20:1 → 10:1) gave a
mixture of 2a and D-2a as a yellow oil (17 mg, 65%). The
isotope effect was determined by integration of the ESI-
HRMS data in consideration of the isotope pattern of 2a. The
deuterated species D-2a and compound 2a were obtained in
a ratio of 4.5:1. According to GP 1 with 2-ethoxy-2-
phenylpyridine (6, 10 mg, 50 mmol), 2-(2-ethoxy-6-
deuterophenyl)pyridine (D-6, 10 mg, 50 mmol) and
phenylboronic acid (24 mg, 0.2 mmol) for 4 h. The ratios of
D-6 to 6 (0.87:1) were determined before the reaction (0 h)
and after a reaction time of 4 h (1.05:1) by integration of the
corresponding ESI-HRMS data in consideration of the
isotope pattern of 6. The kinetic isotope effect was
calculated to be 1.21.
2-(2-Ethoxy-6-deuterophenyl)pyridine (D-6)
2-(2-Ethoxyphenyl)pyridine (6, 93 mg, 0.47 mmol), NBS
(0.10 g, 0.56 mmol) and Pd(OAc)2 (5.4 mg, 24 mol) in
MeCN (10 mL) were heated in a reaction tube at 120 °C for
10 h.22 The solvent was removed under reduced pressure,
and the residue was purified by flash chromatography
(pentane–MTBE, 10:1). Crude 2-(2-bromo-6-ethoxy-
phenyl)pyridine was obtained as a pale yellow oil (96 mg)
and used for the next reaction without any further
characterization. To a solution of crude 2-(2-bromo-6-
ethoxyphenyl)pyridine (86 mg, 0.31 mmol) in THF (10 mL)
at –78 °C was added dropwise n-BuLi (1.3 M solution in
hexanes, 0.48 mL, 0.62 mmol).23 The mixture was allowed
to warm to –40 °C and stirred for 30 min. Then, D2O (0.5
mL) was added and stirring was continued for additional 30
min. The mixture was allowed to warm to r.t., and EtOAc (5
mL) was added. The organic layer was washed with brine,
dried over MgSO4, and the volatiles were removed under
reduced pressure. The crude product was purified by flash
chromatography (pentane–MTBE, 20:1) and D-6 was
obtained as a pale yellow oil (43 mg, 46% over two steps, 94
atom% D determined via ESI-MS). IR (neat): 3036, 2980,
2933, 2881, 2363, 2341, 1578, 1474, 1452, 1421, 1391,
1285, 1250, 1190, 1138, 1111, 1088, 1040, 1026, 990, 924,
874, 812, 795, 746, 733, 679, 611, 552 cm–1. 1H NMR (300
MHz, CDCl3): d = 8.68 (m, 1 H, aryl-H), 7.88 (m, 1 H, aryl-
(20) As a side product the doubly arylated product is always
formed (<15% with respect to the monoarylated compound).
We assume that the primary kinetic isotope effect for the
second arylation and the first arylation should be similar.
Therefore, the measured value of 4.5 is slightly too high
since 2a is consumed faster than D-2a. However, the error
should be smaller than 12%. Hence the primary kinetic
isotope effect for the first arylation is about 4.0–4.5 to 1.
(21) 2-(2,6-Dideuterophenyl)pyridine (D2-1) and 2-(2,6-
Dibromophenyl)pyridine
2-(2-Bromophenyl)pyridine22 (466 mg, 2.0 mmol),
Cu(OAc)2 (363 mg, 2.0 mmol), and 1,1,2,2-tetra-bromo-
Synlett 2008, No. 18, 2841–2845 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Oxidative C–H Arylation of (Hetero)arenes
2845
H), 7.66 (m, 1 H, aryl-H), 7.32 (m, 1 H, aryl-H), 7.16 (m,
7.88; 121.5/7.16; 120.9/7.05; 112.5/6.96; 64.1/4.07; 14.8/
1.36. 1H,13C GHMBC (600 MHz, CDCl3): d(1H)/d(13C) =
156.3/7.80, 7.32, 7.05, 6.96, 4.07; 156.0/7.868, 7.88, 7.66;
149.3/7.66, 7.16; 135.4/8.68, 7.88, 7.80, 7.52; 129.7/7.05;
129.0/7.88, 7.32, 7.05, 6.96; 125.1/8.68, 7.66, 7.16; 121.5/
8.68, 7.88, 7.66; 120.9/6.96; 112.5/7.32, 7.05; 64.1/1.35;
14.8/4.05. ESI-HRMS: m/z calcd for C13H12DNO [M + H]+:
201.1133; found: 201.1129.
1 H, aryl-H), 7.05 (m, 1 H, aryl-H), 6.96 (m, 1 H, aryl-H),
4.07 (q, J = 6.9 Hz, 2 H, CH2), 1.36 (t, J = 6.9 Hz, 2 H, CH3).
13C NMR (600 MHz, CDCl3): d = 156.3 (C), 156.0 (C),
149.3 (CH), 135.4 (CH), 130.8 (C), 129.7 (CH), 129.0 (C),
125.1 (CH), 121.5 (CH), 120.9 (CH), 112.5 (CH), 64.1
(CH2), 14.8 (CH3). 1H{1H} 1D-TOCSY (600 MHz, CDCl3):
d(1H)irr/d(1H)res = 6.96/7.32, 7.05; 8.68/7.88, 7.66, 7.16.
1H,1H GCOSY (600 MHz, CDCl3): d(1H)/d(1H) = 8.86/7.16;
7.88/7.66; 7.66/7.88, 7.16; 7.32/7.05, 6.96; 7.16/8.68, 7.66;
7.05/7.32; 6.96/7.32. 1H,13C GHSQC (600 MHz, CDCl3):
d(1H)/d(13C) = 149.3/8.68; 135.4/7.66; 129.7/7.32; 125.1/
(22) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
Tetrahedron 2006, 62, 11483.
(23) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790.
Synlett 2008, No. 18, 2841–2845 © Thieme Stuttgart · New York

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