Selective palladium-catalyzed aminations on 2-chloro-3-iodo- and 2-chloro-5-iodopyridine

Article abstract of DOI:10.1055/s-2002-35579

Regioselective palladium-catalyzed aminations with anilines on 2-chloro-3-iodo- and 2-chloro-5-iodopyridine have been performed with excellent yields and good selectivity. The use of a large excess of Cs₂CO₃ in combination with Pd-BINAP catalyst was essential to obtain sufficiently fast reactions. The mild conditions permit the presence of base sensitive functional groups. Moreover, the catalytic system developed also allows the arylamination of aryl iodides.

Full text of DOI:10.1055/s-2002-35579

LETTER
1995
Selective Palladium-Catalyzed Aminations on 2-Chloro-3-iodo- and
2-Chloro-5-iodopyridine
P
alladium-Cataly
e
ze
d
A
mina
r
tions on
t
H
alopyridine
U
s
. W. Maes,*a Kristof T. J. Loones,a Tim H. M. Jonckers,a Guy L. F. Lemière,a Roger A. Dommisse,a
Achiel Haemersb
a
Department of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, 2020 Antwerp, Belgium
Fax +32(3)2180233; E-mail: bert.maes@ua.ac.be
b
Department of Medicinal Chemistry, University of Antwerp (UIA), Universiteitsplein 1, 2610 Antwerp, Belgium
Received 13 August 2002
yet.7 Moreover, during the development of intermolecular
Buchwald–Hartwig aminations, aryl iodides have been
pointed out to be less effective substrates than the corre-
sponding aryl bromides (in contrast to the C–C bond
Abstract: Regioselective palladium-catalyzed aminations with
anilines on 2-chloro-3-iodo- and 2-chloro-5-iodopyridine have been
performed with excellent yields and good selectivity. The use of a
large excess of Cs2CO3 in combination with Pd–BINAP catalyst
was essential to obtain sufficiently fast reactions. The mild condi- forming reactions).8–10 All these factors make a selective
tions permit the presence of base sensitive functional groups. More-
amination study on 2-chloro-3-iodopyridine and 2-chloro-
over, the catalytic system developed also allows the arylamination
5-iodopyridine an interesting and not self-evident task.
of aryl iodides.
As a model reaction we chose the palladium-catalyzed
coupling of p-toluidine with 2-chloro-3-iodopyridine. For
this substrate we first tried to use our conditions reported
Key words: palladium, aminations, chloro-iodopyridines, iodo-
benzenes, diarylamines
for the arylamination of chloropyridazin-3(2H)-ones and
dichloropyridines.4,11 Refluxing 2-chloro-3-iodopyridine,
Tin free palladium-catalyzed amination, independently
p-toluidine (1.2 equivalents), 2 mol% Pd–BINAP catalyst
discovered by Buchwald and Hartwig, has established it-
and a large excess of K2CO3 (5 equivalents) as the base in
self as a very powerful tool for the synthesis of arylamines
toluene gave a selective amination in the 3 position. Inter-
including diarylamines.1,2 Diarylamines are of synthetic
estingly, neither 2- nor 2,3-diaminated product was
importance since several applications as pharmaceuticals
formed. However, only a slow reaction rate was observed.
are known. They are indeed considered as ‘privileged
In order to increase the reaction rate, other bases (K3PO4
structures’: single molecular frameworks, able to provide
and Cs2CO3) were screened. In a comparative study using
ligands for diverse receptors.3 As a part of a new synthetic
5 equivalents of K2CO3, K3PO4 and Cs2CO3, the last one
project, our laboratory focuses on the synthesis of aryl-
gave the best results.12 It is important to note that in an ini-
amino substituted pyridines, quinolines and naphthy-
tial study to couple amines with aryl iodides Buchwald
ridines via palladium-catalyzed amination reactions.
also used the Pd–BINAP catalyst system but in this case
Recently, we described a very efficient regioselective pal-
NaOt-Bu was utilized as the base.13 No successful report
ladium-catalyzed amination protocol for the arylamina-
on intermolecular aminations on aryl iodides using milder
tion of dichloropyridines.4 Compounds 2,3-, 2,5- and 2,6-
bases such as Cs2CO3 in combination with Pd–BINAP has
dichloropyridine could be regioselectively aminated in
been published yet.8,14 Remarkably, a large excess of mild
the 2-position with an arylamine yielding 3-, 5- and 6-
base was essential to obtain good results. When 5 equiva-
chloro substituted 2-arylaminopyridines respectively.
lents of Cs2CO3 were used, a yield of 90% of 2-chloro-3-
As a continuation of this selective amination study we
wanted to prepare the isomeric 3-arylamino-2-chloro- and
5-arylamino-2-chloropyridines. Therefore, we studied re-
gioselective palladium-catalyzed amination on easily ac-
cessible 2-chloro-3-iodopyridine and 2-chloro-5-
iodopyridine.5 Palladium-catalyzed C-C bond forming
cross-coupling reactions on 2-chloro-3-iodopyridine and
2-chloro-5-iodopyridine with selective substitution of the
iodine atom have already been reported, but no report of a
similar selective Buchwald–Hartwig C–N bond formation
has appeared up to now.5,6 More generally, to the best of
our knowledge no palladium-catalyzed aminations on
azaheteroaryl iodides have been described in the literature
(4-methylphenylamino)pyridine was obtained after re-
fluxing for 8 hours, whereas the use of 2 equivalents of the
same base gave only a yield of 68% in the same reaction
time. This rate increase in palladium-catalyzed amina-
tions caused by the use of a large excess of base has al-
ready been observed by us in palladium-catalyzed
aminations of dichloropyridines and chloropyridazin-
3(2H)-ones.4,11 Since the excess of base responsible for
the accelerating effect does not dissolve in the reaction
mixture, an interphase mechanism might be involved.
However, the true nature of this effect remains unclear
and will be the subject of further investigation.
Next, we probed the optimized conditions for the coupling
of 2-chloro-3-iodopyridine with other substituted
anilines. Table 1 clearly shows that activated as well as
deactivated anilines can be smoothly coupled with 2-
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,1995,1998,ftx,en;G22902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1996
B. U. W. Maes et al.
LETTER
Table 2 Selective Pd-Catalyzed Amination on 2-Chloro-5-
Table 1 Selective Pd-Catalyzed Amination on 2-Chloro-3-
iodopyridine20–22
iodopyridine20–22
Pd(OAc)2 or
Pd2(dba)3
ligand
Pd(OAc)2 or
H
H
N
Pd2(dba)3
I
I
N
R
R
ligand
R
+
R
+
Cs2CO3
solvent
heat
Cs2CO3
solvent
heat
Cl
N
Cl
N
N
Cl
N
Cl
NH2
NH2
Yield (%)a
Entry
R
Mol% Pd
Mol%
ligand
Yield (%)a
Entry
R
Mol% Pd
Mol%
ligand
1
2
3
4
5
6
7
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3O
4-F
2
2
2
2
2
2
3
2
2
4
4
2
2
3
95b
45c
81c
90c,d
93b
92b
98b
1
2
3
4
5
6
7
8
9
4-CH3
4-CH3
4-CH3
3-CH3
4-CH3O
4-F
2
2
2
2
3
2
2
3
2
2
2
2
2
3
2
2
3
2
92b
97c
97c,d
92b
92b
97b
4-EtOOC
4-EtOOC
2-CN
93b
a All reactions were run overnight (17 hours); reaction times were not
minimized.
80b
b Pd(OAc)2, BINAP, 2-chloro-5-iodopyridine (1.5 mmol), aniline
(1.8 mmol), Cs2CO3 (7.5 mmol), toluene (15 mL), oil bath tempera-
ture 120 °C.
2-Cl
80b (16)e
a All reactions were run overnight (17 hours); reaction times were not
minimized.
c Pd2(dba)3, XANTPHOS, 2-chloro-5-iodopyridine (1.5 mmol),
aniline (1.8 mmol), Cs2CO3 (2.1 mmol), dioxane/triethylamine (2:1,
4.5 mL), oil bath temperature 100 °C.
b Pd(OAc)2, BINAP, 2-chloro-3-iodopyridine (1.5 mmol), aniline
(1.8 mmol), Cs2CO3 (7.5 mmol), toluene (15 mL), oil bath tempera-
ture 120 °C.
d 5 equivalents Cs2CO3 instead of 1.4 equivalents were used.
c Pd2(dba)3, XANTPHOS, 2-chloro-3-iodopyridine (1.5 mmol),
aniline (1.8 mmol), Cs2CO3 (2.1 mmol), dioxane/ triethylamine (2:1,
4.5 mL), oil bath temperature 100 °C.
d 5 equivalents Cs2CO3 instead of 1.4 equivalents were used.
e Yield of diaminated pyridine based on 2-chloro-3-iodopyridine.
lecular palladium-catalyzed amination on aryl iodides up
to 2001 used strong base (t-BuOM) limiting the scope to
non-base sensitive functional groups.13–18 Only recently,
Buchwald’s group thoroughly reinvestigated palladium-
catalyzed aminations on aryl iodides.10 For the synthesis
of diarylamines with base sensitive functionalities Buch-
wald succesfully used 9,9-dimethyl-4,5-bis(diphe-
nylphosphino)xanthene (XANTPHOS) as ligand for the
palladium catalyst in combination with the weak base
Cs2CO3 in a mixture of dioxane and triethylamine as sol-
vent.10 In order to compare our catalytic system with
Buchwald’s we used identical conditions as reported by
Buchwald in the coupling of 2-chloro-3-iodo- and 2-chlo-
ro-5-iodopyridine with p-toluidine [1 mol% Pd2(dba)3, 2
mol% XANTPHOS, p-toluidine (1.2 equivalents),
Cs2CO3 (1.4 equivalents), mixture of dioxane/NEt3 (2:1)].
For the synthesis of 2-chloro-3-(4-methylphenylami-
no)pyridine a similar yield (97% in comparison with 92%)
was obtained with XANTPHOS (Table 1, entries 1 and 2),
whereas with this catalyst, the synthesis of the isomer 2-
chloro-5-(4-methylphenylamino)pyridine gave a very
poor result: overnight reflux gave an incomplete reaction
and an isolated yield of only 45% (Table 2, entry 2).
Doubling the amount of XANTPHOS resulted in a better
yield (81%) (Table 2, entry 3).19 A further slight improve-
ment was obtained by using 5 equivalents of Cs2CO3 in-
stead of 1.4 equivalents (90%) (Table 2, entry 4).
chloro-3-iodopyridine in excellent yields (entries 1, 4–9).
Also base sensitive anilines such as benzocaine (Table 1,
entry 7) and o-aminobenzonitrile (Table 1, entry 8) could
be efficiently coupled under our reaction conditions. Even
the presence of sterical hindrance in the aniline such as in
o-aminobenzonitrile (Table 1, entry 8) and o-chloro-
aniline (Table 1, entry 9) does not seem to hamper the re-
action. Attempts to expand these selective aminations
towards the isomeric substrate 2-chloro-5-iodopyridine
gave similar results (Table 2, entries 1, 5–7). All reactions
were typically run overnight, and a higher loading of
catalyst was taken in those cases where overnight reflux
still gave an incomplete reaction. In all cases selective
substitution of the iodine was observed, and only trace
amounts of the diaminated pyridines could be detected
in the MS analyses of the crude reaction mixtures. A
sole exception was observed, in the coupling reaction
of o-chloroaniline with 2-chloro-3-iodopyridine: the di-
aminated product [2,3-bis(2-chlorophenylamino)pyri-
dine] was isolated in 16% yield (Table 1, entry 9).
As already mentioned before, aryl iodides have been
shown to be less effective substrates than their bromide
counterparts in amination chemistry; reports on intermo-
Synlett 2002, No. 12, 1995–1998 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Aminations on Halopyridines
1997
Table 3 Synthesis of Diarylamines via Pd-Catalyzed Amination on Aryl Iodides23
Pd(OAc)2
R
R'
R
BINAP
N
I
+ R'(R")NH
R"
Cs2CO3
toluene
reflux
Entry
Aryl iodide
Aniline
Mol% Pd
Mol% BINAP
Yield (%)a
Literature yield10
(%)b
EtO2C
N(H)Me
1
2
3
1
1
1
1
1
1
98
98
95
84
86
91
I
N(H)Me
EtO2C
NC
I
CO2Et
NH2
I
a All reactions were run overnight (17 hours); reaction times were not minimized. Pd(OAc)2, BINAP, aryl iodide (1.5 mmol), aniline (1.8
mmol), Cs2CO3 (7.5 mmol), toluene (15 mL), oil bath temperature 120 °C.
b 0.5 mol% Pd2(dba)3, 2 mol% XANTPHOS, aniline, Cs2CO3 (1.4 equivalents), mixture of dioxane/NEt3 (2:1) or dioxane/t-BuOH (2:1), heat.
In testing the applicability of our catalytic system on other
aromatic iodides, we tried to use it for the preparation of
diarylamines: N-(3-carbethoxyphenyl)-N-methylaniline,
N-(4-carbethoxyphenyl)-N-methylaniline and 3-cyano-2 -
carbethoxydiphenylamine (Table 3). Recently, these three
diarylamines were prepared by Buchwald’a group via
the amination of ethyl 3-iodobenzoate and ethyl 4-iodo-
benzoate with N-methylaniline and 3-iodobenzonitrile
with ethyl 2-aminobenzoate respectively using the Pd–
XANTPHOS catalytic system [0.5 mol% Pd2(dba)3, 2
mol% XANTPHOS, aniline, Cs2CO3 (1.4 equivalents),
mixture of dioxane/Et3N (2:1) or dioxane/t-BuOH
(2:1)].10 Gratifyingly, we found that using our reaction
procedure an equal loading of catalyst gave similar re-
sults. As for aminations on chloro-iodopyridines, a large
excess of base was essential to obtain good results. When
5 equivalents of Cs2CO3 were used a yield of 79% of
N-(3-carbethoxyphenyl)-N-methylaniline was obtained
after refluxing for 3 hours, whereas the use of 2 equi-
valents of the same base gave only a yield of 51% in the
same reaction time.
Acknowledgment
Dr. B. Maes thanks the Fund for Scientific Research (FWO-Vlaan-
deren) for an appointment as post-doctoral fellow. The authors wish
to thank the University of Antwerp (RAFO-RUCA) for financial
support, Prof. Dr. E. Esmans and Dr. F. Lemière for the use of their
MS facilities and our technical staff (J. Aerts, J. Schrooten, W. Van
Dongen and J. Verreydt) for their assistance.
References
(1) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348. (b)Louie,J.;Hartwig,
J. F. Tetrahedron Lett. 1995, 36, 3609.
(2) For recent reviews on Pd-catalyzed amination see:
(a) Barañano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem.
1997, 1, 287. (b) Frost, C. G.; Mendonça, P. J. Chem. Soc.,
Perkin Trans. 1 1998, 2615. (c) Hartwig, J. F. Angew.
Chem. Int. Ed. 1998, 37, 2046. (d) Muci, A. R.; Buchwald,
S. L. Top. Curr. Chem. 2002, 219, 131.
(3) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D.
F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D.
J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.;
Hirshfield, J. J. Med. Chem. 1988, 31, 2235. (b) Ariëns, E.
J.; Beld, A. J.; Rodrigues de Miranda, J. F.; Simonis, A. M.
In The Receptors a Comprehensive Treatise; O’Brien, R. D.,
Ed.; Plenum Press: New York, 1979.
In conclusion we have clearly shown that a regioselective
arylamination on 2-chloro-3-iodo- and 2-chloro-5-iodo-
pyridine can be performed using a Pd–BINAP catalytic
system in combination with a large excess of Cs2CO3. The
mild conditions allow the use of base sensitive functional
groups on both coupling partners. The broader use of
this procedure for the palladium-catalyzed amination of
aryl iodides with anilines in general, is another attractive
feature of our methodology.
(4) Jonckers, T. H. M.; Maes, B. U. W.; Lemière, G. L. F.;
Dommisse, R. Tetrahedron 2001, 57, 7027.
(5) 2-Chloro-3-iodo- and 2-chloro-5-iodopyridine were
prepared from the corresponding commercially available
amino derivatives via diazotization and subsequent reaction
with KI: Sakamoto, T.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1985, 33, 4764.
Synlett 2002, No. 12, 1995–1998 ISSN 0936-5214 © Thieme Stuttgart · New York

1998
B. U. W. Maes et al.
LETTER
mL). The filtrate was evaporated and the resulting crude
product was purified by flash column chromatography.
(21) General procedure for the selective Pd-catalyzed aminations
on 2-chloro-3-iodopyridine and 2-chloro-5-iodopyridine
using Pd2(dba)3–XANTPHOS:
(6) Examples of chemoselective palladium-catalyzed C-C
cross-coupling reactions on chloro-iodopyridines:
(a) Mello, J. V.; Finney, N. S. Org. Lett. 2001, 3, 4263.
(b) Baxter P. N. W.; J. Org. Chem.; 2000, 65: 1257.
(c) Muratake, H.; Tonegawa, M.; Natsume, M. Chem.
Pharm. Bull. 1998, 46, 400. (d) Rocca, P.; Marsais, F.;
Godard, A.; Quéguiner, G. Tetrahedron 1993, 49, 49.
(e) Sakamoto, T.; Kondo, Y.; Watanabe, R.; Yamanaka, H.
Chem. Pharm. Bull. 1986, 34, 2719.
(7) Just before submitting this manuscript an article appeared
dealing with Pd-catalyzed aminations on 3-iodo-6-
arylpyridazines. PdCl2(dppf) catalyst in combination with
t-BuONa was used in the reported amination reactions
(Hartwig conditions).16 These conditions do not allow a
large functional group compatibility on both coupling
partners: Parrot, I.; Ritter, G.; Wermuth, C. G.; Hibert, M.
Synlett 2002, 1123.
(8) For Pd–BINAP-catalyzed aminations of aryl bromides with
Cs2CO3 as base see: Wolfe, J. P.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1144.
(9) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158.
(10) Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560.
(11) Košmrlj, J.; Maes, B. U. W.; Lemière, G. L. F.; Haemers, A.
Synlett 2000, 1581.
A round bottom flask was charged with Pd2(dba)3 (Acros,
0.015 mmol), XANTPHOS (Strem Chemicals, 0.03 mmol or
0.06 mmol) and freshly distilled dioxane (Acros, stabilized
99+%; dried over sodium/benzophenone, 3 mL). The
mixture was flushed with nitrogen for 10 minutes under
magnetic stirring. In another round bottom flask chloro-
iodopyridine (0.359 g, 1.5 mmol), aniline (1.8 mmol) and
Cs2CO3 (Acros, 99.5%, 2.1 mmol or 7.5 mmol) were
weighed. Then, the Pd2(dba)3–XANTPHOS solution was
added, and the flask was rinsed well with triethylamine
(Aldrich, 99%; stored over K2CO3, 1.5 mL). The resulting
mixture was flushed with nitrogen for 5 minutes under
magnetic stirring and subsequently heated in an oil bath
under vigorous magnetic stirring (oil bath temperature 100
°C, N2 atmosphere). After overnight reflux the mixture was
cooled down to room temperature. The solid material was
filtered off and washed well with CH2Cl2 (200 mL). The
filtrate was evaporated and the resulting crude product was
purified by flash column chromatography.
(22) Spectroscopic data of selected compounds:
(12) The reactions were followed with GC using diphenyl ether
as internal standard. Aliquots of the reaction mixtures were
monitored after 4, 8, 24 and 48 hours. Reactions were
considered as finished if less than 5% of starting material
was present: K2CO3 (48 hours), K3PO4 (24 hours) and
Cs2CO3 (8 hours).
(13) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066.
(14) For the palladium-catalyzed N-arylation of sulfoximines, the
use of aryl iodides with Pd–BINAP as catalyst in
combination with a mild carbonate base has been reported.
To ensure product formation in acceptable yields the use of
additives (LiBr, LiCl, AgOTf) was essential: Bolm, C.;
Hildebrand, J. P. J. Org. Chem. 2000, 65, 169.
2-Chloro-3-(4-methylphenylamino)pyridine (Table 1,
entries 1–3):
H (400 MHz, CDCl3): 7.78 (dd, J = 4.6, 1.7 Hz, 1 H, H-6),
7.34 (dd, J = 8.1, 1.7 Hz, 1 H, H-4), 7.14 (d, J = 8.1 Hz, 2 H,
H-3 ,5 ), 7.03 (d, J = 8.1 Hz, 2 H, H-2 ,6 ), 7.00 (dd, J = 8.1
Hz, 4.6 Hz, 1 H, H-5), 6.08 (br s, 1 H, NH), 2.32 (s, 3 H,
CH3); C (400 MHz, CDCl3): 138.5, 138.3, 138.0, 137.6,
133.7, 130.0, 122.9, 121.9, 120.4, 20.6.
2-Chloro-5-(4-methylphenylamino)pyridine (Table 2,
entries 1–4):
H (400 MHz, CDCl3): 8.13 (dd, J = 3.1 Hz, 0.5 Hz, 1 H, H-
6), 7.35 (dd, J = 8.5 Hz, 3.1 Hz, 1 H, H-4), 7.20 (dd, J = 8.5
Hz, 0.5 Hz, 1 H, H-3), 7.19 (d, J = 8.4 Hz, 2 H, H-3 ,5 ), 7.04
(d, J = 8.4 Hz, 2 H, H-2 ,6 ), 5.74 (br s, 1 H, NH), 2.39 (s, 3
H, CH3); C (400 MHz, CDCl3): 141.5, 140.1, 138.7, 138.3,
132.8, 130.2, 125.7, 124.2, 119.9, 20.7.
(15) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133.
(16) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118,
7217.
(17) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369.
(23) General procedure for the synthesis of diarylamines via Pd-
catalyzed aminations on iodobenzenes:
(18) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307.
(19) Buchwald originally used a double amount of XANTPHOS
(Pd/2L instead of Pd/L)
(20) General procedure for the selective Pd-catalyzed aminations
on 2-chloro-3-iodopyridine and 2-chloro-5-iodopyridine
using Pd(OAc)2–BINAP:
A round bottom flask was charged with Pd(OAc)2 (Acros,
0.0034 g, 0.015 mmol), ( )-BINAP (Strem Chemicals,
0.0094 g, 0.015 mmol) and toluene (Acros, 99%, 5 mL). The
mixture was flushed with nitrogen for 10 minutes under
magnetic stirring. In another round bottom flask aryl iodide
(1.5 mmol), aniline (1.8 mmol) and Cs2CO3 (Acros, 99.5%,
2.444 g, 7.5 mmol) were weighed. Then, the Pd(OAc)2–
BINAP solution was added, and the flask was rinsed well
with an additional amount of toluene (10 mL). The resulting
mixture was flushed with nitrogen for 5 minutes under
magnetic stirring and subsequently heated in an oil bath
under vigorous magnetic stirring (oil bath temperature 120
°C, N2 atmosphere). After overnight reflux the mixture was
cooled down to room temperature. The solid material was
filtered off and washed well with CH2Cl2 (200 mL). The
filtrate was evaporated and the resulting crude product was
purified by flash column chromatography. The
A round bottom flask was charged with Pd(OAc)2 (Acros,
0.03 mmol or 0.045 mmol), ( )-BINAP (Strem Chemicals,
0.03 mmol or 0.045 mmol) and toluene (Acros, 99%, 5 mL).
The mixture was flushed with nitrogen for 10 minutes under
magnetic stirring. In another round bottom flask chloro-
iodopyridine (0.359 g, 1.5 mmol), aniline (1.8 mmol) and
Cs2CO3 (Acros, 99.5%, 2.444 g, 7.5 mmol) were weighed.
Then, the Pd(OAc)2–BINAP solution was added, and the
flask was rinsed well with an additional amount of toluene
(10 mL). The resulting mixture was flushed with nitrogen for
5 minutes under magnetic stirring and subsequently heated
in an oil bath under vigorous magnetic stirring (oil bath
temperature 120 °C, N2 atmosphere). After overnight reflux
the mixture was cooled down to room temperature. The solid
material was filtered off and washed well with CH2Cl2 (200
characterization data of N-(3-carbethoxyphenyl)-N-
methylaniline, N-(4-carbethoxyphenyl)-N-methylaniline
and 3-cyano-2 -carbethoxydiphenylamine were identical
with those reported in the literature.10
Synlett 2002, No. 12, 1995–1998 ISSN 0936-5214 © Thieme Stuttgart · New York