Selective palladium-catalyzed aminations on dichloropyridines

Article abstract of DOI:10.1016/S0040-4020(01)00659-7

Palladium-catalyzed amination proved to be a valuable strategy for the selective introduction of aromatic and heteroaromatic amines, including aminopyridines and aminodiazines, on dichloropyridines. The use of mild amination conditions resulted in maximum selectivity and excellent base sensitive functional group tolerance.

Full text of DOI:10.1016/S0040-4020(01)00659-7

TETRAHEDRON
Pergamon
Tetrahedron 57 ?2001) 7027±7034
Selective palladium-catalyzed aminations on dichloropyridines
p
Á
Tim H. M. Jonckers, Bert U. W. Maes, Guy L. F. Lemiere and Roger Dommisse
Department of Chemistry, University of Antwerp ꢀRUCA), Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
Received 2 April 2001; revised 25 May 2001; accepted 14 June 2001
AbstractÐPalladium-catalyzed amination proved to be a valuable strategy for the selective introduction of aromatic and heteroaromatic
amines, including aminopyridines and aminodiazines, on dichloropyridines. The use of mild amination conditions resulted in maximum
selectivity and excellent base sensitive functional group tolerance. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
amination reactions including 2-chloropyridine, 3-chloro-
pyridine and 4-chloropyridine, as well as their brominated
analogues.11±13 To the best of our knowledge, no dihalo-
genated pyridine derivative ?with the exception of 2,6-
dibromopyridine13) was used in amination chemistry. We
were surprised by the absence of such a study and conse-
quently we decided to probe the applicability of an ami-
nation strategy in the selective functionalization of
pyridines. While this work was in progress, Desmarets
reported the Ni?0)-catalyzed synthesis of substituted chloro-
aminopyridines starting from dichloropyridines.14 However,
minor selectivity was obtained and fairly high catalyst
loadings were necessary. Moreover the use of relatively
toxic nickel has to be regarded as an additional drawback
of this method.15
The modi®cation of the pyridine nucleus is a versatile
research area, which still attracts a considerable amount of
interest in modern organic chemistry. Due to its presence in
numerous natural products and biologically active
substances,1 the pyridine moiety is still regarded as one of
the most interesting heteroaromatic ring systems. Not-
withstanding the fact that a multitude of different reactions
on pyridine and its derivatives are known, as illustrated by
2
3
Â
the marvellous work of Katritzky and Queguiner, there is
still a need for new approaches towards pyridine func-
tionalization. Independently discovered by Buchwald and
Hartwig, the Pd-catalyzed amination reaction has estab-
lished itself as one of the most versatile and powerful
synthetic strategies currently available.4,5 The amination
protocol has successfully been applied in the synthesis of
numerous arylamino-substituted arenes and more recently,
starts to ®nd its way in heterocyclic chemistry as exempli-
®ed by the synthesis of N6-aryl 20-deoxyadenosine ana-
logues by Lakshman,6 and of the potent H1-antihistaminic
norastemizole by Senanayake.7 As in the case of other
Pd-catalyzed cross-coupling reactions such as the Suzuki-8
and Stille-reaction,9 the Pd-catalyzed amination protocol
was ®rst elaborated on iodo- and bromo?hetero)arenes.10
However, better understanding of the reaction mechanism
as a result of detailed study, resulted in the development of
reaction conditions which turned out to be suitable for
unactivated chloro?hetero)arene substrates. Especially, the
development and use of new and more electron rich
ligands like 1,3-bis?diphenylphosphino)propane ?DPPP)
and 2-?dicyclohexylphosphino)-20-?N,N-dimethylamino)-
1,10-biphenyl ?DCHPDMAB) turned out to be a factor of
utmost importance.11 A number of halogenated pyridine
derivatives have been successfully used in Pd-catalyzed
2. Results and discussion
Very recently, our laboratory16 reported very mild ami-
nation conditions for the preparation of substituted
4-amino-3?2H)-pyridazinones using a large excess of
K2CO3 or Cs2CO3 as the base instead of NaOtBu or
KOtBu. Although it has been reported that the latter two
give the fastest reactions, their high basisity often causes
problems, especially when base-sensitive substrates are
employed.4d,10a,17 Therefore we decided to investigate the
use of our mild conditions for the selective Pd-catalyzed
aminations of dichloropyridines. As a starting point we
studied the cross-coupling of different dichloropyridines
i.e. 2,3-dichloropyridine ?1a), 2,5-dichloropyridine ?1b)
and 2,6-dichloropyridine ?1c) with 2-aminopyridine ?2a),
3-aminopyridine ?2b) and 4-aminopyridine ?2c).
As can be seen from Table 1, the reactions proceeded
smoothly, affording the reaction products in good yield.
Noteworthy is the fact that in every reaction the mono
substituted product was formed exclusively and regio-
selectively. Di-aminated products could not be detected,
even after prolonged reaction times in the presence of an
Keywords: aminations; palladium; pyridines; heteroaromatic amines;
regioselectivity.
Corresponding author. Tel.: 132-3-218-02-29; fax: 132-3-218-02-33;
e-mail: dommisse@ruca.ua.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020?01)00659-7

7028
T. H. M. Jonckers et al. / Tetrahedron 57 ꢀ2001) 7027±7034
Table 1. Synthesis of substituted chloropyridines ?3) using mild amination conditions
Entry
Dichloropyridine ?1)
Aminopyridine ?2)
Time ?h)
Yielda ?%)
Reaction product ?3)b
1
2
3
4
5
6
7
1a
1a
1a
1c
1b
1c
1c
2a
2b
2c
2a
2b
2c
2b
18
18
18
2
2
2
93
71
80
4
4
4
4
3a
3b
3c
3d
3e
3f
56
48
64
62
c
2
3g
a
b
c
Yields reported are those of analytical pure compounds.
General reaction conditions: 2mol% Pd?OAc) 2, 2mol% BINAP, 1.2equiv. amine, 20 equiv. K 2CO3.
In this case 6 mol% of Pd?OAc)2 and BINAP were used.
excess of amine.18 As reported before, the use of a large
amount of K2CO3 was found to be crucial to get the reaction
to completion.19
worthwhile to investigate the use of other heteroaromatic
amines in more detail because such an approach would
allow access to potentially interesting new heterocycles.
Reaction of 2,3-dichloropyridine ?1a) with 2-aminoquino-
line ?2d), 3-amino-6-ethoxypyridazine21 ?2e), 2-amino-4,6-
dimethylpyrimidine ?2f) and aminopyrazine ?2g) under our
mild conditions, afforded the expected reaction products in
good yield.
Encouraged by these promising results we examined, as a
second part of this work, the possibility of introducing other
amines on the pyridine skeleton. Surprisingly, a thorough
literature search revealed that little work has been done on
amination reactions with heteroaromatic amines. To the best
of our knowledge only the three isomeric aminopyridines
?2a±c) had been used so far.13,20 Therefore, we felt it was
As illustrated in Scheme 1, heterocyclic amines turned
out to be valuable coupling partners. As before, in every
Scheme 1. Amination of 2,3-dichloropyridine ?1a) with different heteroaromatic amines.

T. H. M. Jonckers et al. / Tetrahedron 57 ꢀ2001) 7027±7034
Table 2. Introduction of substituted aniline derivatives onto dichloropyridines
7029
Entry
Dichloropyridine ?1)
Substituted aniline ?2)
Substituent R
Time ?h)
Yielda ?%)
Reaction product ?3)b
1
2
3
4
1a
1a
1c
1b
2h
2i
2j
2k
4±NO2±
4-CH3O±
2-CN±
18
18
40
18
80
93
41
64
3l
3m
3n
3o
4-COOEt
a
Yields reported are those of analytical pure compounds.
General reaction conditions: 2mol% Pd?OAc) 2, 2mol% BINAP, 1.2equiv. amine, 20 equiv. K 2CO3.
b
case, the amination proceeded regioselectively in the
2-position.
seems very unlikely. In control experiments we tried to
prepare ?3-chloro-2-pyridyl)?4-methoxyphenyl)amine ?3m)
and ?2-pyridyl)?3-chloro-2-pyridyl)amine ?3a) in the
absence of Pd?OAc)2. Both reactions failed and it can there-
fore be concluded that reaction via nucleophilic aromatic
substitution can be ruled out.
To further investigate the scope of this amination approach
towards pyridine modi®cation we turned our attention to
substituted aniline derivatives as amine sources. To
demonstrate the general suitability of our method, we
chose four different anilines i.e. p-nitroaniline ?2h), p-anisi-
dine ?2i), 2-aminobenzonitrile ?2j) and benzocaine ?2k) as
test substrates. The former two are interesting because of
their extreme electronic properties while the latter two
incorporate base sensitive functional groups. Table 2
summarizes the results obtained.
To complete our study on Pd-catalyzed amination on
dichloropyridines, we tried to use 3,5-dichloropyridine
?1d) as a starting material. However, we anticipated that
we might run into trouble due to the unfavourable positions
of the chlorine atoms. Indeed, after reacting 3,5-dichloro-
pyridine ?1d) with 2-aminopyridine ?2a) using the con-
ditions described above, no amination product could be
detected. Since the 3 and 5 positions are the most deacti-
vated, we thought that using a more electron rich ligand
might solve the problem. So we tried DPPP, DCHPDMAB
and tricyclohexylphosphine ?TCHP) instead of BINAP.
Disappointedly, we learnt that none of these ligands were
really suitable even with higher loadings of catalyst.
Gratifyingly, we found that the use of the electron rich
As can be seen from Table 2, both electron rich and electron
poor anilines are easily introduced ?entries 1, 2). Also the
presence of base sensitive functional groups is well tolerated
?entries 3, 4). The successful coupling of 2,3-dichloro-
pyridine ?1a) with the strongly deactivated p-nitroaniline
?2h) is an indication of the intervention of Pd in this reac-
tion. Indeed, formation of ?3-chloro-2-pyridyl)?4-nitro-
phenyl)amine ?3l) via a nucleophilic substitution reaction
ligand
2-?dicyclohexylphosphino)biphenyl
?DCHPB)
Table 3. Optimisation of the amination of 3,5-dichloropyridine
Entry
Pd-source
Ligand
Base
2CO3 ?20 equiv.)
Solvent
Reaction time ?h)
Yield ?3p) ?%)
1
2
3
4
5
6
7
8
Pd?OAc)2 2mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 2mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
Pd?OAc)2 4 mol%
BINAP 2mol%
DCHPDMAB 4 mol%
TCHP 4 mol%
K
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
24
24
24
24
36
36
36
36
36
36
36
0
0
0
0
15
0
0
40
0
0
0
K2CO3 ?20 equiv.)
K 2CO3 ?20 equiv.)
K2CO3 ?20 equiv.)
K2CO3 ?20 equiv.)
t-BuONa ?1.5 equiv.)
Cs2CO3 ?20 equiv.)
K2CO3 ?20 equiv.)
Cs2CO3 ?20 equiv.)
t-BuONa ?1.5 equiv.)
t-BuOK ?1.5 equiv.)
DPPP 4 mol%
DCHPB 8 mol%
DCHPB 8 mol%
DCHPB 8 mol%
DCHPB 8 mol%
DCHPB 8 mol%
DCHPB 8 mol%
DCHPB 8 mol%
9
10
11

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T. H. M. Jonckers et al. / Tetrahedron 57 ꢀ2001) 7027±7034
Scheme 2. Reaction of 3,5-dichloropyridine ?1d) with benzocaine ?2k).
resulted in the formation of a small amount ?15%) of the
desired compound. Stimulated by this observation we
decided to optimise other parameters in search of better
reaction conditions ?Table 3).
amination of dichloropyridines. This approach might give
access to useful intermediates for the synthesis of natural
products and hitherto unknown pharmaceuticals.
4. Experimental
As can be seen from the table the use of dioxane as the
solvent instead of toluene had a signi®cant effect on the
yield ?entry 8). Also important to note is the fact that neither
NaOtBu nor Cs2CO3 were effective ?entries 6, 7, 9 and 10)
even when DCHPB is used as the ligand. Since we noted
that the cation of the base might be important ?compare
entries 5 with 7 and 8 with 9) we also tried KOtBu ?entry
11). However the reaction was not successful.
All reagents were purchased from commercial sources
?Acros, Aldrich, Lancaster) and were used as such. Dioxane
was distilled from sodium benzophenone before use.
Column chromatography was carried out using Kieselgel
60 ?Merck), 0.040±0.063 mm. Thin layer chromatography
was performed on pre-coated ALUGRAMw SIL G/UV254
Kieselgel 60 0.25 mm TLC-plates. NMR spectra were
recorded on a Varian Unity 400 MHz spectrometer in
CDCl3 as the solvent unless otherwise stated. In every
case TMS was used as the internal standard. Chemical shifts
are given in ppm and J values in Hz. Multiplicity is
indicated using the following abbreviations: d for a doublet,
t for a triplet, m for a multiplet etc. In those cases where
standard 1H and 13C measurements were insuf®cient,
additional 2D-measurements ?i.e. HETCOR, LR-HETCOR,
COSY) were performed for complete structure elucidation.
IR spectra were recorded on a Bruker Vector 22 spectro-
meter. For mass spectrometric analysis, samples were
dissolved in CH3OH containing 0.1% formic acid and
diluted to a concentration of approx. 1025 mol/L. 1 mL
injections were directed to the mass spectrometer at a ¯ow
rate of 5 mL/min CH3OH ?0.1% Formic acid), using the
CapLC HLPC system ?Waters, Millford). Product ion
spectra and exact mass measurements were performed
To probe the applicability of these optimised reaction con-
ditions, we also tried to introduce an arylamino substituent
on 3,5-dichloropyridine ?1d). Reaction with benzocaine
?2k) afforded ?5-chloro-3-pyridyl)?4-ethoxycarbonylphenyl)-
amine ?3q) in moderate yield as shown in Scheme 2.
The observations presented in this work regarding the selec-
tivity of Pd-catalyzed aminations on dichloropyridines can
be nicely explained considering the following theoretical
model. As illustrated above, whenever a chlorine atom is
present in the 2-position, it is preferentially substituted
regardless of the position of the other chlorine atom. This
difference in reactivity of the 2-position in comparison to
the 3- and 5-positions in pyridines is analogous to obser-
vations made in classic heterocyclic chemistry.22 This
similarity can be understood if one considers the oxidative
addition ?the ®rst step in Pd-catalyzed cross-coupling
reactions) as a nucleophilic aromatic substitution.23 This
also explains the fact that substitution of a chlorine atom
in the 3-position requires more electron rich ligands which
results in an increased nucleophilicity of the Pd-catalyst
thereby enhancing the possibility of oxidative addition.
The exclusive formation of mono-aminated products in
Pd-catalyzed aminations on 2,6-dichloropyridine ?1c) is
most probably the result of the more electron rich nature
of the intermediate mono aminated chloropyridine ?arising
from the electron donating nature of the introduced amino
substituent) which prevents a second oxidative addition.
on
a quadrupole/orthogonal-acceleration time-of-¯ight
?Q/oaTOF) tandem mass spectrometer ?qTof 2, Micromass,
Manchester, UK) equipped with a standard electrospray
ionisation ?ESI) interface. Cone voltage ?35 V) and
capillary voltage ?3.3 kV) were optimised on one compound
and used for the series of experiments. Fragmentation was
induced by low energy collisional activation using an Ar
gas using a collision energy of 30 eV. Melting points
were determined on a BuÈchi B-545 apparatus and are
uncorrected.
4.1. Typical procedure for the Pd-catalyzed aminations
on 2,3-dichloropyridine, 2,5-dichloropyridine and 2,6-
dichloropyridine.
3. Conclusions
In conclusion, we have shown that selective palladium-cata-
lyzed amination reactions can serve as a valuable protocol
in the functionalization of pyridines. Mild conditions in
combination with low catalyst loading allows the selective
A round bottom ¯ask was ¯ushed with nitrogen and charged
with Pd?OAc)2 ?13.5 mg, 0.06 mmol, 2%), ?^)-BINAP
?37.5 mg, 0.06 mmol, 2%) and toluene ?10 mL). The
mixture was stirred under nitrogen for 10 min. In another

T. H. M. Jonckers et al. / Tetrahedron 57 ꢀ2001) 7027±7034
7031
round bottom ¯ask dichloropyridine ?0.441 g, 3 mmol),
amine ?3.6 mmol, 1.2equiv.) and K 2CO3 ?8.28 g, 60
mmol) were weighed. Then, the Pd?OAc)2/BINAP solution
was added, and the ¯ask was rinsed with an additional
17 mL toluene. The resulting mixture was subsequently
re¯uxed in an oil bath under N2 with vigorous stirring
until the starting dichloropyridine had disappeared as
judged by TLC and DCI-MS. After cooling down, the
solid material was ®ltered off and washed with 100 mL
CH2Cl2. The solvent was evaporated and the resulting
crude product was puri®ed by ¯ash column chromatography
using the speci®ed eluent.
?ddd, 1H, Jˆ8.4, 7.3, 2.0 Hz, H-4), 7.91 ?br, 1H, N±H),
8.23 ?dd, 1H, Jˆ4.2, 2.0 Hz, H-6); dC: 109.7 ?C-30), 112.2
0
?C-3), 115.9 ?C-50), 117.1 ?C-5), 138.1 ?C-4), 140.2?C-4 ),
0
147.9 ?C-6), 149.2?C-6 ), 153.6 ?C-2), 154.0 ?C-20); LRMS
?ES): 170, 143, 112, 96, 78; HRMS ?ESI) for C10H9N3Cl
[M1H]1 found: 206.0476, calcd: 206.0485; C10H8N3Cl
calcd: C, 58.41; H, 3.92; N, 20.43, found: C, 58.26; H,
4.06; N, 20.53.
4.1.5. /3-Pyridyl)/5-chloro-2-pyridyl)amine /3e). eluent:
CH2Cl2/MeOH ?9/1); yield: 0.300 g ?48%); white solid;
mp 165.18C; nmax?KBr): 3297, 3186, 1644, 1580, 1485,
1423 cm21; dH: 6.72?br, 1H, N±H), 6.73 ?d, 1H, Jˆ
8.8 Hz, H-30), 7.26 ?dd, 1H, Jˆ8.2, 4.0 Hz, H-5), 7.48
?dd, 1H, Jˆ8.8, 2.6 Hz, H-40), 7.96 ?dd, 1H, Jˆ8.2,
1.2Hz, H-4), 8.18 ?d, 1H, Jˆ2.6 Hz, H-60) 8.28 ?dd, 1H,
Jˆ4.0, 1.2Hz, H-6), 8.58 ?s, 1H, H-2); dC: 110.3 ?C-30),
123.0 ?C-50), 123.8 ?C-5), 126.6 ?C-4), 137.2 ?C-3), 137.8
?C-40), 141.8 ?C-2), 143.9 ?C-6), 146.8 ?C-60), 153.7 ?C-20);
LRMS ?ES): 189, 179, 170, 166, 144, 130, 112, 94, 78, 68;
HRMS ?ESI) for C10H9N3Cl [M1H]1 found: 206.483,
calcd: 206.485; C10H8N3Cl calcd: C, 58.41; H, 3.92; N,
20.43, found: C, 58.55; H, 3.87; N, 20.21.
4.1.1. /2-Pyridyl)/3-chloro-2-pyridyl)amine /3a). eluent:
CH2Cl2/MeOH ?96/4); yield: 0.573 g ?93%); white solid;
mp 48.88C; nmax?KBr): 3417, 1589, 1525, 1437, 766,
740 cm21; dH: 6.76 ?dd, 1H, Jˆ7.9, 4.8 Hz, H-50), 6.90
?ddd, 1H, Jˆ7.3, 4.9, 0.9 Hz, H-5), 7.59 ?dd, 1H, Jˆ7.9,
1.4 Hz, H-40), 7.66 ?ddd, 1H, Jˆ8.6, 7.3, 1.8 Hz, H-4), 7.82
?br, 1H, N±H), 8.16 ?dd, 1H, Jˆ4.8, 1.4 Hz, H-60), 8.26
?ddd, 1H, Jˆ4.9, 1.8, 0.9 Hz, H-6), 8.44 ?dd, 1H, Jˆ8.6,
0.9 Hz, H-3); dC: 112.6 ?C-3), 116.4 ?C-50), 117.0 ?C-30),
117.9 ?C-5), 137.1 ?C-40), 138.0 ?C-4), 145.7 ?C-60), 148.1
?C-6), 150.3 ?C-20), 153.1 ?C-2); LRMS ?ES): 170, 112, 96,
78, 51; HRMS ?ESI) for C10H9ClN3 [M1H]1 found:
206.0473, calcd: 206.0485; C10H8ClN3 calcd: C, 58.41; H,
3.92; N, 20.43, found: C, 58.49; H, 3.87; N, 20.44.
4.1.6. /4-Pyridyl)/6-chloro-2-pyridyl)amine /3f). eluent:
CH2Cl2/MeOH ?9/1); yield: 0.399 g ?64%); white solid;
mp 180.58C; nmax?KBr): 3294, 3177, 1638, 1584, 1459,
1354, 1163, 780 cm21; dH ?acetone-d6): 6.92?m, H2,
H-30, H-50), 7.67 ?m, 3H, H-40, H-3), 8.39 ?d, 2H, Jˆ
5.6 Hz, H-2), 9.02 ?br, 1H, N±H); dC ?acetone-d6): 110.2
?C-3), 112.3 ?C-30), 115.3 ?C-50), 140.5 ?C-40), 147.6 ?C-60),
148.7 ?C-4), 150.3 ?C-2), 155.2 ?C-20); LRMS ?ES): 179,
170, 143, 114, 112, 79; HRMS ?ESI) for C10H9N3Cl [M1
H]1 found: 206.469, calcd: 206.0485; C10H8N3Cl calcd: C,
58.41; H, 3.92; N, 20.43, found: C, 58.25; H, 3.80; N, 20.60.
4.1.2. /3-Pyridyl)/3-chloro-2-pyridyl)amine /3b). eluent:
CH2Cl2/MeOH ?96/4); yield: 0.440 g ?71%); white solid;
mp 91.68C; nmax?KBr): 3257, 3108, 3063, 1605, 1526,
1434 cm21; dH: 6.76 ?dd, 1H, Jˆ7.7, 5.0 Hz, H-50), 7.05
?br, 1H, N±H), 7.25 ?dd, 1H, Jˆ8.4, 4.6 Hz, H-5), 7.58
?dd, 1H, Jˆ7.7, 1.6 Hz, H-40), 8.12?dd, 1H, Jˆ5.0,
1.6 Hz, H-60), 8.24 ?ddd, 1H, Jˆ8.4, 2.6, 1.5 Hz, H-6),
8.26 ?dd, 1H, Jˆ4.6, 1.5 Hz, H-4), 8.71 ?d, 1H, Jˆ2.6 Hz,
0
H-2); dC:116.2?C-5 ), 116.5 ?C-30), 123.5 ?C-5), 126.7 ?C-
4.1.7. /3-Pyridyl)/6-chloro-2-pyridyl)amine /3g). eluent:
CH2Cl2/MeOH ?9/1); yield: 0.385 g ?62%); white solid;
mp 142.18C; nmax?KBr): 3294, 3179, 1639, 1530, 1481,
1429, 1346, 780, 698 cm21; dH: 6.68 ?d, 1H, Jˆ8.0 Hz,
H-30), 6.80 ?d, 1H, Jˆ7.6 Hz, H-50), 6.94 ?br, 1H, N±H),
7.28 ?dd, 1H, Jˆ8.4, 4.7 Hz, H-5), 7.45 ?dd, 1H, Jˆ8.0,
7.6 Hz, H-40), 7.98 ?ddd, 1H, Jˆ8.4, 2.5, 1.1 Hz, H-4),
8.29 ?dd, 1H, Jˆ4.7, 1.1 Hz, H-6), 8.57 ?d, 1H, Jˆ2.5 Hz,
H-2); dC: 107.0 ?C-30), 115.30 ?C-50), 123.9 ?C-5), 127.1
?C-4), 136.9 ?C-3), 140.2?C-4 ), 142.1 ?C-2), 144.2 ?C-6),
149.9 ?C-60), 155.4 ?C-20); LRMS ?ES): 189, 170, 166, 143,
116, 112, 79; HRMS ?ESI) for C10H9N3Cl [M1H]1 found:
206.468, calcd: 206.0485; C10H8N3Cl calcd: C, 58.41; H,
3.92; N, 20.43, found: C, 58.72; H, 3.61; N, 20.28.
4), 136.7 ?C-30), 137.1 ?C-40), 141.8 ?C-2), 143.8 ?C-6),
145.9 ?C-60), 151.0 ?C-20); LRMS ?ES): 189, 179, 170,
130, 112, 94, 78, 68; HRMS ?ESI) for C10H9N3Cl [M1
H]1 found: 206.0473, calcd: 206.0485; C10H8N3Cl calcd:
C, 58.41; H, 3.92; N, 20.43, found: C, 58.46; H, 3.98; N,
20.31.
4.1.3. /4-Pyridyl)/3-chloro-2-pyridyl)amine /3c). eluent:
CH2Cl2/MeOH ?9/1); yield: 0.483 g ?80%); white solid;
mp 156.38C; nmax?KBr): 3252, 3162, 1603, 1514, 1424,
1335, 1211 cm21; dH: 6.82?dd, 1H, Jˆ7.7, 4.9 Hz, H-50),
7.20 ?br, 1H, N±H), 7.61±7.63 ?m, 3H, H-3, H-40), 8.20 ?dd,
1H, Jˆ4.9, 1.6 Hz, H-60), 8.44 ?d, 2H, Jˆ6.0 Hz, H-2); dC:
0
112.9 ?C-3), 117.1 ?C-50), 117.2?C-3 ), 137.3 ?C-40), 145.9
?C-60), 146.8 ?C-4), 150.3 ?C-20), 150.6 ?C-2); LRMS ?ES):
179, 170, 143, 116, 112, 79; HRMS ?ESI) for C10H9N3Cl
[M1H]1 found: 206.0474, calcd: 206.0485; C10H8N3Cl
calcd: C, 58.41; H, 3.92; N, 20.43, found: C, 58.50; H,
3.98; N, 20.30.
4.1.8. /2-Quinolyl)/3-chloro-2-pyridyl)amine /3h). eluent:
CH2Cl2/MeOH ?96/4); yield: 0.64 g ?83%); white solid; mp
119.58C; nmax?KBr): 3400, 1592, 1502, 1430, 1331, 1028,
793 cm21; dH: 6.79 ?dd, 1H, Jˆ7.8, 4.9 Hz, H-50), 7.36 ?t,
1H, Jˆ7.5, 7.5 Hz, H-6), 7.61 ?dd, 1H, Jˆ7.8, 1.1 Hz, H-40),
7.62?dd, 1H, Jˆ8.0, 7.5 Hz, H-7), 7.72?d, 1H, Jˆ7.5 Hz,
H-5), 7.83 ?d, 1H, Jˆ8.0 Hz, H-8), 8.05 ?br, 1H, N±H), 8.09
?d, 1H, Jˆ8.9 Hz, H-4), 8.18 ?dd, 1H, Jˆ4.9, 1.1 Hz, H-60),
8.63 ?d, 1H, Jˆ8.9 Hz, H-3); dC: 114.1 ?C-3), 116.9 ?C-50),
117.3 ?C-30), 124.3 ?C-6), 125.8 ?C-4a), 127.2 ?C-8), 127.6
?C-5), 129.9 ?C-7), 137.4 ?C-40), 137.9 ?C-4), 145.7 ?C-60),
147.4 ?C-8a), 150.3 ?C-20), 152.5 ?C-2); LRMS ?ES): 220,
4.1.4. /2-Pyridyl)/6-chloro-2-pyridyl)amine /3d). eluent:
CH2Cl2/MeOH ?96/4); yield: 0.338 g ?56%); white solid;
mp 71.28C; nmax?KBr): 3258, 3166, 1591, 1529, 1463,
1437, 1159, 765 cm21; dH: 6.82?dd, 1H, Jˆ6.7, 1.4 Hz,
H-50), 6.84 ?ddd, 1H, Jˆ7.3, 4.2, 0.9 Hz, H-5), 7.42 ?dd,
1H, Jˆ8.4, 0.9 Hz, H-3), 7.52?m, 2H, H-3 0, H-40), 7.61

7032
T. H. M. Jonckers et al. / Tetrahedron 57 ꢀ2001) 7027±7034
146, 128; HRMS ?ESI) for C14H10ClN3 [M1H]1 found:
256.0618, calcd: 256.0642; C14H9ClN3 calcd: C, 65.76; H,
3.94; N, 16.43, found: C, 65.58; H, 3.89; N, 16.66.
823, 744 cm21; dH: 3.80 ?s, 3H, ±OCH3), 6.64 ?dd, 1H,
Jˆ7.8, 4.7 Hz, H-50), 6.81 ?br, 1H, N±H), 6.90 ?d, 2H, Jˆ
8.9 Hz, H-3), 7.48 ?d, 2H, Jˆ8.9 Hz, H-2), 7.53 ?dd, 1H,
Jˆ7.8, 1.6 Hz, H-40), 8.07 ?dd, 1H, Jˆ4.7 Hz, 1.6, H-60);
dC: 55.7 ?±OCH3), 114.5 ?C-3), 114.7 ?C-50), 115.8 ?C-30),
122.9 ?C-2), 132.9 ?C-1), 136.7 ?C-40), 146.1 ?C-60), 152.1
?C-20), 156.1 ?C-4); LRMS ?ES): 203, 191, 185, 157, 123,
108; HRMS ?ESI) for C12H12ClN2O [M1H]1 found:
235.0617, calcd: 235.0638; C12H11ClN2O calcd: C, 61.41;
H, 4.72; N, 11.94, found: C, 61.32; H, 4.69; N, 12.06.
4.1.9. /3-/6-Ethoxypyridazinyl))/3-chloro-2-pyridyl)amine
/3i). eluent: Heptane/EtOAc ?2.5/1); yield: 0.41 g ?60%);
white solid; mp 129.28C; nmax?KBr): 3404, 3061, 2979,
1595, 1519, 1436, 1403, 1294, 1031, 572 cm21; dH: 1.41
?t, 3H, Jˆ7.1 Hz, ±CH3), 4.51 ?q, 2H, Jˆ7.1 Hz, ±CH2±),
6.79 ?dd, 1H, Jˆ7.6, 4.7 Hz, H-50), 6.96 ?d, 1H, Jˆ9.7 Hz,
H-5), 7.62?dd, 1H, Jˆ7.6, 1.6 Hz, H-40), 7.88 ?br, 1H,
N±H), 8.10 ?dd, 1H, Jˆ4.7, 1.6 Hz, H-60), 8.57 ?d, 1H,
Jˆ9.7 Hz, H-4); dC: 14,75 ?±CH3), 63.09 ?±CH2±), 116.7
?C-50), 117.0 ?C-30), 118.9 ?C-5), 122.6 ?C-4), 137.4 ?C-40),
4.1.14. /6-Chloro-2-pyridyl)/2-cyanophenyl)amine /3n).
eluent: Heptane/EtOAc ?2.5/1); yield: 0.27 g ?40%); white
solid; mp 154.88C; nmax?KBr): 3334, 2227, 1616, 1590,
1448, 1159, 942, 773, 741 cm21; dH: 6.77 ?d, 1H, Jˆ
0
145.6 ?C-60), 150.2?C-2 ), 152.6 ?C-3), 162.2 ?C-6); LRMS
0
8.2Hz, H-3 ), 6.90 ?d, 1H, Jˆ7.6 Hz, H-50) 6.99 ?br, 1H,
?ES): 224, 178, 166, 153, 143, 131, 127, 112, 100, 92, 80;
HRMS ?ESI) for C11H12ClN4O [M1H]1 found: 251.0690,
calcd: 251.0700; C11H11ClN4O calcd: C, 52.70; H, 4.42; N,
22.35, found: C, 52.65; H, 4.31; N, 22.51.
N±H), 7.05 ?ddd, 1H, Jˆ8.9, 7.5, 0.9 Hz, H-4), 7.55 ?m, 3H,
H-40, H-5, H-6), 8.24 ?d, 1H, Jˆ7.5 Hz, H-3); dC: 101.6
?C-2), 108.9 ?C-30), 116.6 ?C-50), 117.1 ?CN), 119.3 ?C-3),
122.3 ?C-4), 132.9 ?C-6), 134.2 ?C-5), 140.3 ?C-40), 143.0
?C-60), 149.8 ?C-20), 154.0 ?C-1); LRMS ?ES): 194, 167,
140, 130, 112, 94, 76, 66; HRMS ?ESI) for C12H9ClN3
[M1H]1 found: 230.0486, calcd: 230.0485; C12H8ClN3
calcd: C, 62.76; H, 3.51; N, 18.30, found: C, 62.60; H,
3.36; N, 18.45.
4.1.10. /2-/4,6-Dimethylpyrimidyl))/3-chloro-2-pyridyl)-
amine /3j). eluent: CH2Cl2/MeOH ?9/1); yield: 0.637 g
?90%); light yellow solid; mp 173.28C; nmax?KBr): 3186,
3025, 1606, 1424, 1339, 794 cm21; dH: 2.41 ?s, 6H,
±CH3), 6.62?s, 1H, H-5), 6.89 ?dd, 1H, Jˆ7.6, 4.7 Hz,
0
H-50), 7.63 ?dd, 1H, Jˆ7.6, 1.2Hz, H-4 ), 7.68 ?br, 1H,
0
4.1.15. /5-Chloro-2-pyridyl)/4-ethoxycarbonylphenyl)-
amine /3o). eluent: Heptane/EtOAc ?2.5/1); yield: 0.532 g
?64%); white solid; mp 171.88C; nmax?KBr): 3324, 3215,
1680, 1473, 1366, 1174, 1020, 825, 767 cm21; dH: 1.39
?tr, 3H, Jˆ7.1 Hz, ±CH3), 4.35 ?q, 2H, Jˆ7.1 Hz,
±OCH2±), 6.81 ?br, 1H, N±H), 6.82?d, 1H, Jˆ8.8 Hz,
H-30), 7.40 ?d, 2H, Jˆ8.6 Hz, H-2), 7.51 ?dd, 1H, Jˆ8.8,
2.6 Hz, H-40), 7.99 ?d, 2H, Jˆ8.6 Hz, H-3), 8.20 ?d, 1H,
Jˆ2.6 Hz, H-60); dC: 14.5 ?±CH3) 60.8 ?±OCH2±), 111.0
?C-30), 117.7 ?C-2), 123.4 ?C-50), 124.1 ?C-4), 131.3 ?C-3),
137.7 ?C-40), 144.7 ?C-1), 147.0 ?C-60), 153.1 ?C-20), 166.4
?CvO); LRMS ?ES): 249, 231, 203, 169, 93; HRMS ?ESI)
for C14H14ClN2O2 [M1H]1 found: 277.0763, calcd:
277.0744; C14H13ClN2O2 calcd: C, 60.77; H, 4.74; N,
10.12, found: C, 60.89; H, 4.59; N, 10.29.
N±H), 8.30 ?dd, 1H, Jˆ4.7, 1.2Hz, H-6 ); dC: 24,20
?±CH3), 114.1 ?C-5), 118.6 ?C-50), 120.1 ?C-30), 137.6
?C-40), 146.6 ?C-60), 149.4 ?C-20), 158.9 ?C-2), 168.2
?C-4, C-6); LRMS ?ES): 199, 153, 107, 82; HRMS ?ESI)
for C11H12ClN4 [M1H]1 found: 235.0738, calcd: 235.0750;
C11H11ClN4 calcd: C, 56.30; H, 4.72; N, 23.87, found: C,
56.42; H, 4.78; N, 23.99.
4.1.11. /2-Pyrazyl)/3-chloro-2-pyridyl)amine /3k). eluent:
CH2Cl2/MeOH ?96/4); yield: 0.583 g ?91%); white solid;
mp 76.38C; nmax?KBr): 3401, 1596, 1534, 1421, 1033,
1006 cm21; dH: 6.86 ?dd, 1H, Jˆ7.8, 4.9 Hz, H-50), 7.64
?dd, 1H, Jˆ7.8, 1.6 Hz, H-40), 7.72?br, 1H, N±H), 8.21
?m, 3H, H-5, H-6, H-60), 9.81 ?d, 1H, Jˆ1.2Hz, H-3); dC:
0
117.0 ?C-30), 117.3 ?C-50), 136.2?C-3), 137.4 ?C-4 ), 138.2
?C-5), 142.1 ?C-6), 145.9 ?C-60), 149.4 ?C-2), 149.7 ?C-20);
LRMS ?ES): 171, 153, 139, 118, 112, 79, 69, 52; HRMS
?ESI) for C9H8ClN4 [M1H]1 found: 207.0435, calcd:
206.0437; C9H7ClN4 calcd: C, 52.31; H, 3.41; N, 27.11,
found: C, 52.25; H, 3.28; N, 27.06.
4.2. Typical procedure for Pd-catalyzed aminations on
3,5-dichloropyridine.
A round bottom ¯ask was ¯ushed with nitrogen and charged
with Pd?OAc)2 ?27.5 mg, 0.12 mmol, 4%), DCHPB ?84 mg,
0.24 mmol, 8%) and dry dioxane ?10 mL). The mixture was
stirred under nitrogen for 10 minutes. In an other round
bottom ¯ask dichloropyridine ?0.441 g, 3 mmol), amine
?3.6 mmol, 1.2equiv.) and K 2CO3 ?8.28 g, 60 mmol) were
weighed. Then, the Pd?OAc)2/DCHPB solution was added,
and the ¯ask was rinsed with an additional 17 mL dioxane.
The resulting mixture was subsequently heated to re¯ux
under N2 with vigorous stirring until the starting dichloro-
pyridine had disappeared as judged by TLC and DCI-MS.
After cooling down, the solid material was ®ltered off and
washed with 100 mL CH2Cl2. The solvent was evaporated
and the resulting crude product was puri®ed by ¯ash column
chromatography using the speci®ed eluent.
4.1.12. /3-Chloro-2-pyridyl)/4-nitrophenyl)amine /3l).
eluent: CH2Cl2; yield: 0.593 g ?80%); yellow solid; mp
145.28C; nmax?KBr): 3400, 1582, 1499, 1424, 1330, 1108,
840, 747 cm21; dH: 6.87 ?dd, 1H, Jˆ7.8, 4.7 Hz, H-50), 7.38
?br, 1H, N±H), 7.65 ?dd, 1H, Jˆ7.8, 1.6 Hz, H-40), 7.84 ?d,
2H, Jˆ9.1 Hz, H-2), 8.20 ?d, 2H, Jˆ9.1 Hz, H-3), 8.21 ?dd,
1H, Jˆ4.7, 1.6 Hz, H-60); dC: 117.3 ?C-30), 117.5 ?C-50),
118.0 ?C-4), 125.4 ?C-3), 137.4 ?C-40), 142.0 ?C-4), 145.9
?C-60), 146.0 ?C-1), 150.0 ?C-20); LRMS ?ES): 203, 191,
169; HRMS ?ESI) for C11H9ClN3O2 [M1H]1 found:
250.0375, calcd: 250.0383; C11H8ClN3O2 calcd: C, 52.92;
H, 3.23; N, 16.83, found: C, 52.75; H, 3.33; N, 16.95.
4.1.13. /3-Chloro-2-pyridyl)/4-methoxyphenyl)amine /3m).
eluent: CH2Cl2; yield: 0.656 g ?93%); yellow oil;
4.2.1. /2-Pyridyl)/5-chloro-3-pyridyl)amine /3p). eluent:
EtOAc; yield: 0.248 g ?40%); white solid; mp 191.38C;
n
max?KBr): 3419, 3004, 2833, 1601, 1507, 1244, 1031,

T. H. M. Jonckers et al. / Tetrahedron 57 ꢀ2001) 7027±7034
7033
Â
F.; Queguiner, G. Tetrahedron 2000, 56, 1349. ?b) Mongin, F.;
 Â
Mongin, O.; Trecourt, F.; Godard, A.; Queguiner, G.
n
max?KBr): 3295, 3185, 2918, 1641, 1574, 1484, 1446,
1425, 1346, 1109, 774 cm21; dH ?DMSO-d6): 6.71 ?ddd,
1H, Jˆ7.3, 5.1, 0.9 Hz, H-5), 6.87 ?dd, 1H, Jˆ8.4, 0.9 Hz,
H-3), 7.62?ddd, 1H, Jˆ8.4, 7.3, 2.0 Hz, H-4), 8.08 ?d, 1H,
Jˆ2.2 Hz, H-20), 8.41 ?dd, 1H, Jˆ5.1, 2.0 Hz, H-6), 8.54 ?t,
1H, Jˆ2.2, 2.2 Hz, H-40), 8.61 ?d, 1H, Jˆ2.2 Hz, H-60),
9.50 ?br, 1H, N±H); dC ?DMSO-d6): 112.2 ?C-3), 116.3
?C-5), 123.3 ?C-40), 131.2?C-5 0), 138.4 ?C-4), 138.6
?C-60), 139.3 ?C-20), 140.0 ?C-30), 147.8 ?C-6), 155.6
?C-2); LRMS ?ES): 170, 143, 116, 78; HRMS ?ESI) for
C10H9N3Cl [M1H]1 found: 206.490, calcd: 206.0485;
C10H8N3Cl calcd: C, 58.41; H, 3.92; N, 20.43, found: C,
58.26; H, 3.78; N, 20.55.
Tetrahedron Lett. 1996, 37, 6695. ?c) Mongin, O.; Rocca,
Â
P.; Thomasditdumont, L.; Trecourt, F.; Marsais, F.; Godard,
Â
A.; Queguiner, G. J. Chem. Soc., Perkin Trans. 1 1995, 19,
Â
2503. ?d) Gungor, T.; Marsais, F.; Queguiner, G. J. Organo-
Â
met. Chem. 1981, 215, 139. ?e) Queguiner, G. J. Heterocycl.
Chem. 2000, 37, 615.
4. ?a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348. ?b) Wolfe, J. P.; Rennels,
R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. ?c) Wolfe,
J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. ?d) Wolfe, J. P.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1144.
4.2.2.
/5-Chloro-3-pyridyl)/4-ethoxycarbonylphenyl)-
5. ?a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
?b) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F.
J. Org. Chem. 1997, 62, 1268. ?c) Mann, G.; Hartwig, J. F.;
amine /3q). eluent: Heptane/EtOAc ?1/1); yield: 0.462g
?56%); white solid; mp 166.28C; nmax?KBr): 3325, 1678,
1603, 1576, 1338, 1292, 1181, 1100, 831, 773 cm21; dH:
1.38 ?tr, 3H, Jˆ7.1 Hz, ±CH3), 4.36 ?q, 2H, Jˆ7.1 Hz,
±OCH2±), 6.36 ?br, 1H, N±H), 7.06 ?d, 2H, Jˆ8.8 Hz,
H-2), 7.51 ?t, 1H, Jˆ2.2, 2.2 Hz, H-40), 7.98 ?d, 2H,
Jˆ8.8 Hz, H-3), 8.19 ?d, 1H, Jˆ2.2 Hz, H-20), 8.32?d,
1H, Jˆ2.2 Hz, H-60); dC: 14.5 ?±CH3) 60.9 ?±OCH2±),
116.4 ?C-2), 124.0 ?C-4), 124.8 ?C-40), 131.8 ?C-3), 132.4
?C-50), 139.2?C-6 0), 142.0 ?C-20), 145.9 ?C-1), 166.3
?CvO), ?C-30 was not observed); LRMS ?ES): 249, 231,
214, 203, 169, 127; HRMS ?ESI) for C14H14ClN2O2 [M1
H]1 found: 277.0753, calcd: 277.0744; C14H13ClN2O2
calcd: C, 60.77; H, 4.74; N, 10.12, found: C, 60.66; H,
4.56; N, 9.94.
Â
Driver, M. S.; Fernandez-Rivas, C. J. Am. Chem. Soc. 1998,
120, 827. ?d) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
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Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A. J. Am.
Chem. Soc. 2000, 122, 4618.
6. Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. O.
J. Am. Chem. Soc. 1999, 121, 6090.
7. Hong, Y.; Tanoury, G. J.; Wilkinson, H. S.; Bakale, R. P.;
Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 1997, 38,
5607.
8. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
9. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
10. For reviews on cross-coupling reactions including amination,
see: ?a) Frost, C. G.; MendoncËa, P. J. Chem. Soc., Perkin
Acknowledgements
Trans. 1 1998, 2615. ?b) Baran
Äano, D.; Mann, G.; Hartwig,
J. F. Curr. Org. Chem. 1997, 1, 287. ?c) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 1996, 61, 1133. ?d) Wolfe,
J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066.
11. Wolfe, J. P.; Timori, H.; Sadighi, J. P.; Ying, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158.
We would like to thank J. Verreydt, J. Schrooten, N.
Verhaert, V. Van Heurck, W. Van Lierde, W. Van Dongen,
Á
F. Lemiere and K. Loones for their technical assistance. The
authors would like to thank Professor Dr E. Esams for the
use of his MS-facilities. T. Jonckers would like to thank the
`Vlaams Instituut voor de bevordering van het Wetens-
chappelijk Technologisch onderzoek in de industrie
?IWT)' for a scholarship. T. Jonckers and Dr B. Maes are
grateful to the foundation `Rosa Blanckaert' for receiving
research grants.
12. ?a) Marcoux, J. F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem.
1997, 62, 1568. ?b) Nishiyama, M.; Yamamoto, T.; Koie, Y.
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Liu, Y.; Muchowski, J. M.; Putman, D. G. Tetrahedron Lett.
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?hetero)arylchlorides see: ?d) Cho, Y. H.; Park, J. C.
Tetrahedron Lett. 1997, 38, 8331. For the use of 2-chloro-
quinoline in Pd-catalyzed C±C bond forming reactions see
for instance: ?e) Ciufolini, M. A.; Mitchell, J. W.; Roschangar,
F. Tetrahedron Lett. 1996, 37, 8281.
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