Metal assisted synthesis of mono and diamino substituted pyridines

Article abstract of DOI:10.1016/j.tet.2011.04.060

A microwave assisted Buchwald-Hartwig amination protocol is reported for a series of dihalopyridine precursors. Using this procedure, selective substitution of one halogen by aryl or alkylamines is possible in very short time, usually 30 min. Mild base (K₂CO₃) can be used successfully, which broadens the substrate scope. The second halogen can then be substituted using alkylamines under nucleophilic substitution condition or via a Suzuki-Miyaura cross-coupling reaction. The target compounds are potential inducers of cardiomyogenesis as innovative approach in regenerative medicine.

Full text of DOI:10.1016/j.tet.2011.04.060

Tetrahedron 67 (2011) 4169e4178
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Metal assisted synthesis of mono and diamino substituted pyridines
*
€
Moumita Koley, Michael Schnurch , Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A microwave assisted BuchwaldeHartwig amination protocol is reported for a series of dihalopyridine
precursors. Using this procedure, selective substitution of one halogen by aryl or alkylamines is possible
in very short time, usually 30 min. Mild base (K2CO3) can be used successfully, which broadens the
substrate scope. The second halogen can then be substituted using alkylamines under nucleophilic
substitution condition or via a SuzukieMiyaura cross-coupling reaction. The target compounds are po-
tential inducers of cardiomyogenesis as innovative approach in regenerative medicine.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 18 March 2011
Received in revised form 13 April 2011
Accepted 15 April 2011
Available online 21 April 2011
Keywords:
Amination
Cross-coupling
Heterocycles
Palladium
Catalysis
1. Introduction
activities, in particular it can be used in the treatment of hepatitis
C5a,b as well as in the treatment of hypercholesterolemia.5c
The pyridine ring system is generally considered as a most im-
portant heteroaromatic ring system due to its presence in numer-
ous natural products and biologically active substances.1 Amongst
pyridine containing compounds N-aryl/alkyl amino substituted
pyridines are interesting targets due to their presence in various
bioactive compounds with diverse activity. For example, com-
pounds of the general structure 1 were reported as a new class of
antitumor agents,2 substance 2 displayed inhibition of the vascular
endothelial growth factor receptor (VEGFR-2) tyrosine kinase3 and
structure 3 was reported as a phosphodiesterase IV inhibitor
(Fig. 1).4 All of these compounds contain 4-arylamino substituted
pyridine moieties. Compound 4 exhibits multiple and diverse
Consequently, the synthesis of N-aryl/alkyl pyridinamines has
attractedmuch attention inrecent years. The most frequentlyapplied
methods are nucleophilic substitution6 and BuchwaldeHartwig
amination.7,8 Bothmethods yieldthedesiredproducts anditdepends
on the specific problem, which one performs better. For instance,
introduction of amines in 3-position of pyridine can be carried out
successfully with Pd-catalyzed amination protocols, whereas nucle-
ophilic substitution is extremely difficult. In 2- and 4-position both
methods can be applied and again the specific problem often dictates
the method of choice.
BuchwaldeHartwig aminations on a series of dihalopyridines
(2,3-, 2,4-, 2,6-, and 3,5) are presented within this contribution.
Another aim of the current contribution was the synthesis of
aminopyridines, which resemble the structure of cardiogenols AeD
(Fig. 2). These compounds were previously reported by Wu et al. to
induce the growth of heart muscle cells from P19 stem cells.9 This
was the first report of synthetic small molecules with a car-
diomyogenic effect, i.e., transformation of, e.g., a stem cell into
cardiomyocytes. This is a very interesting novel biological activity,
since the heart usually displays a very limited regenerative capacity
after injury compared to other tissues,10 and opens up novel per-
spectives for treatments in regenerative medicine.
The common structural feature of cardiogenols contains a py-
rimidine core substituted with aryl- and alkylamines in positions 2
and 4. The present study aimed at developing a modular synthesis
for structural analogs by applying the biomimetic strategy of het-
eroatom deletion, consequently, considering corresponding 2,6- or
2,4-diaminated pyridines (I and II) as target structure (Fig. 3).
Fig. 1. Biologically active compounds containing the 4-aminopyridine moiety.
€
* Corresponding author. E-mail address: mschnuerch@ioc.tuwien.ac.at (M. Schnurch).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.060

4170
M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
donating and electron withdrawing) amines also proceeded
smoothly with good yield.13 Although regiospecific, this protocol
has two major drawbacks: a large excess (usually approx. 20 equiv)
of base (K2CO3) is required to achieve complete conversion and
rather long reaction times (18 h typically) are necessary. The
aforementioned protocol did not work for 3,5-dichloropyridine as
precursor and more electron rich ligands and a longer reaction time
(18e36 h) were necessary to accomplish the coupling step due to
the unfavorable positions of chlorine atoms.
Finally, CeN coupling reactions at position 4 of pyridine are
poorly covered in the literature17,18 and the conversion of a 2,4-
dihalopyridine was reported only briefly19; the selectivity and
generality of this transformation was not further elaborated. We
have recently disclosed a selective method for the CeN cross-
coupling reaction in position 4 of 2-fluoro-4-iodopyridine within
a preliminary study, which also allowed to decrease reaction time
and amount of base employing the Pd(OAc)2/BINAP system. This
method was now investigated in the BuchwaldeHartwig coupling
of other dihalopyridines in detail.
Fig. 2. Cardiogenols.
2.2. BuchwaldeHartwig coupling on 2,3-dichloropyridine
Recently, we reported on the BuchwaldeHartwig, Suzu-
kieMiyaura, and LiebeskindeSrogl coupling reactions of 2,3-
dichloropyridine.20 There, the optimized amination procedure18
could be applied as well. In comparison to the previously dis-
closed literature protocol13 requiring 20 equiv of base (K2CO3) and
long reaction times (w18 h) to obtain full conversion and good
yields the reaction time could be significantly shortened with this
microwave assisted21 method (typically 30 min). Additionally, the
amount of base could also be decreased to 3.5 equiv making the
process much more efficient. Naturally, in case of 2,3-dichloropyr-
idine, the CeN bond formation takes place in the more activated
2-position selectively (Scheme 1). The new protocol (2 mol %
Pd(OAc)2, 2 mol % (þ/ꢀ) BINAP, 3.5 equiv K2CO3) was then applied to
a series of dihalopyridines. BINAP was chosen as ligand since it gave
good yields in all cases and is considerably cheaper than other
ligands used for the BuchwaldeHartwig coupling reaction. It is also
noteworthy that the widely applied stronger bases NaOtBu or KOtBu
could be avoided. Although these stronger bases have been reported
to give sometimes faster reactions,16 their high basicity causes
problems when base sensitive substrates are employed. An addi-
tional advantage of this protocol is that all reagents are not sensitive
to air, hence, manipulation of all reaction partners could be con-
ducted at ambient conditions avoiding troublesome handling in a
glove box; simple flushing of the reaction vessel with argon before
sealing was sufficient to ensure reproducible and good yields.
Fig. 3. General structure of de-aza analogs to cardiogenols as target compounds.
2. Results and discussions
2.1. BuchwaldeHartwig coupling reactions on
dihalopyridines
Among heterocycles, pyridine certainly represents a privileged
scaffold and is present in many biological active compounds (e.g.,
alkaloids). Due to the prominent role of pyridine in medicinal
chemistry, methods for efficiently decorating this heterocyclic
scaffold are highly important and BuchwaldeHartwig reactions of
pyridine halides have been investigated, in particular using chlo-
rinated and brominated compounds.8 However, only few examples
of amination reactions on dihalogenated pyridines were reported
in the literature using either palladium11 or nickel catalysts.12 2,6-
Dichloropyridine, 2,3-dichloropyridine, and 3,5-dichloropyridine
were successfully applied in selective CeN cross-coupling reactions
with aromatic amines.13 In case of symmetric 2,6- and 3,5-
dichloropyridine, only one CeN cross-coupling took place leading
to a defined product, whereas 2,3-dichloropyridine reacted selec-
tively at the more activated 2-position.
The most commonly used catalysts for BuchwaldeHartwig re-
actions are based on chelating phosphines, such as BINAP. Mixtures
of Pd2(dba)3 or Pd(OAc)2, and BINAP catalyze the cross-coupling of
amines with a variety of aryl bromides.8 In addition, aryl iodides,
chlorides, and triflates can also be used as substrates. Recent re-
ports have described the use of other bulky and more electron rich
phosphine ligands.8b,14 However, the BINAP catalyst system is still
important as this is one of the most active and general catalysts for
the coupling of aryl halides with primary amines.15 Additionally,
the BINAP catalyst system operates well in the presence of weak
bases, such as cesium or even potassium carbonate allowing for
a high level of functional group tolerance.16 According to literature
reports, the reactions of 2,3-dichloropyridine, 2,6-dichloropyridine,
and 2,5-dichloropyridine with 2/3/4-aminopyridine proceeded
smoothly (Pd(OAc)2 (2 mol %), BINAP (2 mol %), K2CO3 (20 equiv)
refluxing in toluene for 18 h), with yields between 48 and 93%.13
Reaction of dichloropyrimidines with other substituted (electron
Scheme 1. Reaction of 2,3-dichloropyridine.
2.3. BuchwaldeHartwig coupling on 2,6-dichloropyridine
Also in the case of 2,6-dichloropyridine, the microwave assisted
protocol performed well. Literature reports that only one CeN bond
formation took place and no 2,6-diaminated products were
observed under BuchwaldeHartwig conditions again using a large
excess of base and long reaction times (w24 h).13 Our microwave
assisted protocol worked well also on this starting material and

M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
4171
a series of products was prepared in good yields within a short
period of time (Scheme 2).
Table 1 summarizes the obtained results. Both, electron rich
(entries 1e4) and electron poor (entries 6 and 7) anilines were
easily introduced. Also, the presence of a base sensitive functional
group was well tolerated (entry 7). An amide was also used to
couple with the 2,6-dichloropyridine to investigate if this com-
pound class can also be used as starting materials (entry 12), but in
this case the yield of product was only 11%; even longer reaction
time did not give an improved yield. Encouraged by the success of
this amination protocol, some heteroaromatic amines were also
Scheme 2. Reaction of 2,6-dichloropyridine.
Table 1
BuchwaldeHartwig coupling on 2,6-dichloropyridine
Entry
RNH2
Time (min)
30
Product
Yield (%)
72
O
O
1
N
H
N
l
C
H2N
6a
O
O
2
3
30
30
77
77
N
N
l
C
H
H2N
6b
6c
O
O
N
N
N
N
l
C
H
H2N
H
N
H
N
4
30
79
N
N
l
C
H
H2N
6d
N
N
l
C
5
6
30
30
76
53
H
H2N
6e
l
C
l
C
N
H
N
l
C
H2N
6f
Et
O2C
Et
COO
7
8
30
30
66
58
N
N
l
C
H
H2N
6g
N
N
N
l
C
H
H2N
N
6h
N
N
H
N
l
C
9
30
71
N
H2N
(continued on next page)
6i

4172
M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
Table 1 (continued )
Entry
RNH2
Time (min)
Product
Yield (%)
65
N
N
N
H
N
l
C
10
30
H2N
6j
l
C
N
N
N
S
11
12
45
45
73
11
NH
N
NH2
S
6k
c
NHA
N
Cl
O
6l
used to couple with 2,6-dichloropyridines (Table 1). Amino-
pyridines bearing substituents in o, m, and p-position gave good
yields (entries 8e10) and a similar result was obtained with 4-
phenylthiazole-2-amine (entry 12).
Product 6a carrying 4-methoxyaniline was of special interest as
intermediate for the synthesis of the pyridine analog to Cardiogenol
C, since substitution of the remaining chlorine at 6-position with
ethanolamine will give the target compound.
2.5. BuchwaldeHartwig coupling on 2-fluoro-4-iodopyridine
The formation of CeN bonds in 4-position of pyridine is an
important topic from a synthetic point of view since 4-amino-
pyridines represent a frequently encountered structural motif in
biologically active compounds (e.g., 1 and 2). Recently, we have
demonstrated the feasibility of microwave mediated amination in
this position in a preliminary study.18 For syntheses of 4-amino
substituted pyridine derivatives, the most obvious and convenient
2,4-dihalopyridine starting material would be 2,4-dichloropyridine
(9) (Scheme 4) as it is commercially available and cheap. However,
in terms of reactivity the 2- and the 4-positions in pyridine are
quite similar and mixture of products could be obtained. This was
confirmed when the CeN cross-coupling reaction of 2,4-dichlor-
opyridine (Scheme 4) was investigated. As could be expected, the
reaction of 9 with p-anisidine provided both 2- and 4-amino
substituted products 10a and 10b in approx. equimolar ratios
(based on GCeMS), however, in less than 10% yield.
2.4. BuchwaldeHartwig coupling on 3,5-dichloropyridine
Extending our investigations, symmetrical 3,5-dichloropyridine
was used as starting material. According to literature reports more
electron rich ligands and longer reaction times (18e36 h) were
required for the coupling step due to the unfavorable positions of
chlorine atoms;13 no amination product was detected with 2-
aminopyridine using BINAP as ligand. Several bulky and electron
rich ligands, such as 1,3-bis(diphenylphosphino)propane, tricyclo-
hexylphosphino and 2-(dicyclohexylphosphino)biphenyl (DCHPB)
were tested and the best yield could be achieved using DCHPB as
ligand.13 In our hands, applying the above outlined conditions
(Pd(OAc)2, BINAP, K2CO3) under microwave irradiation on 3,5-
dichloropyridine yielded the desired products without any prob-
lems in comparable yields to literature reports (employing more
sophisticated and expansive ligands) (Scheme 3).13
Scheme 4. Reaction of 2,4-dichloropyridine.
Consequently, two different halides need to be placed in posi-
tions 2 and 4 to facilitate selective substitution at C-4 by an
increased reactivity of the halide at this site. In this regard, 2-fluoro-
4-iodopyridine was chosen as substrate, which was prepared
according to a literature protocol starting from commercially
available and relatively cheap 2-fluoropyridine in high yield.22 It
was anticipated that amination will take place preferentially in
4-position under Pd-catalyzed reaction conditions. However, since
high temperatures are used in the protocol developed within this
work for the BuchwaldeHartwig step, a competing nucleophilic
substitution in 2-position could be a possible side reaction. When
carrying out the first experiment using p-anisidine as amine com-
ponent, it was already found that neither nucleophilic substitu-
tion nor BuchwaldeHartwig coupling took place in 2-position
and amination progressed exclusively in 4-position in 63% yield
(Table 2, entry 1); no formation of 2,4-diaminated product was
observed (Scheme 5).
Scheme 3. Reaction of 3,5-dichloropyridine.
As only difference, extended microwave irradiation reaction
times (2 h) were necessary and the conversion was not complete
even after 2 h. The reaction time was not prolonged beyond 2 h due
to partial decomposition of products. Compound 8a, was synthe-
sized in 41% yield (lit. 40%) and compound 8b with 53% (lit. 56%).13
Due to the much shorter reaction time and much cheaper ligand as
well as much lower amounts of base these results represent a sig-
nificant an improvement of the existing protocol.

M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
4173
Table 2
Amination of 2-fluoro-4-iodopyridine in position 4 via BuchwaldeHartwig amination
Entry RNH2 Time (min)
Product
Yield (%)
O
N
O
O
1
30
63
75
F
N
H
H2N
11a
NH
O
2
30
F
N
F
H2N
11b
H
N
3
4
30
30
65
83
N
H2N
11c
O
H
N
F
O
N
H2N
11d
H
N
F
l
C
5
6
7
30
45
45
52
69
78
N
l
C
H2N
11e
H
N
F
Et
COO
N
E
tOOC
H2N
11f
H
N
F
N
C
N
N
C
H2N
11g
H
N
F
O
N
N
8
30
84
N
O
H2N
11h
HN
9
45
52
H2N
N
F
11i
HN
N
O
O
10
45
56
H2N
F
(continued on next page)
11j

4174
M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
Table 2 (continued )
Entry
RNH2
Time (min)
Product
Yield (%)
H
N
N
N
N
11
12
30
30
66
H2N
N
F
F
11k
H
N
79
N
N
H2N
11l
S
N
HN
N
N
S
13
30
48
NH2
F
11m
F
16 ha
52
N
N
14
HN
11n
I
15
16 hb
42
N
N
HN
11o
a
Reaction was carried out at 100 ꢁC for 16 h in a heating block.
Reaction was carried out 130 ꢁC for 16 h in a heating block.
b
this transformation. Benzylamine (entry 9) and 4-methox-
ybenzylamine (entry 10) both gave reasonable conversion and no
other side products were isolated. However, in this case the yield
was somewhat lower and longer reaction times were required
(45 min). Additionally, the scope of heterocyclic amines as coupling
partners in the CeN cross-coupling protocol was also investigated.
All precursors provided access to CeN coupling products (entries
11e13, Table 3) upon selective reaction at position 4 in moderate to
good yields. Also in the case of 11m (entry 13) the reaction pro-
gressed smoothly and with complete conversion. However,
a product and amine displayed similar Rf values complicating
chromatographic purification and decreasing the isolated yield. In
another example, piperidine was investigated as example for
a secondary aliphatic amine. The corresponding product 11n was
obtained in reasonable yield (entry 14) as well but different re-
action conditions had to be applied. A lower temperature (100 ꢁC)
and conventional heating were necessary to give the 4-substituted
product 11n. It was found that temperatures above 130 ꢁC pro-
moted nucleophilic substitution at the fluorine in 2-position to
become the predominant reaction pathway toward 2-substituted
product 11o (entry 15). A ratio of 5:1 (according to GCeMS) of
4-iodo-2-(piperidin-1-yl)pyridine (11o) and 11n was obtained. It
can be concluded that at higher temperatures the activation energy
barrier for the nucleophilic substitution was exceeded and then the
reaction rate of the nucleophilic substitution was higher compared
Scheme 5. Reaction of 2-fluoro-4-iodopyridine.
A
series of substituted aniline derivatives were coupled
employing the established conditions in order to assess the scope of
the protocol. All reactions proceeded smoothly, affording the re-
action products in good yields.18 Product 11a (entry 1, Table 2)
carrying the 4-methoxyaniline substituent in position 4 is again of
special interest since nucleophilic substitution of fluorine with
ethanolamine will enable access to another pyridine derivative of
Cardiogenol
studies.
C important for structureeactivity relationship
This protocol was successful regardless of the nature of the
amine used as coupling partner. Electron rich (entries 1, 2, 4, and 8)
as well as electron poor (entries 5e7) anilines were well tolerated
under the reaction conditions to produce the desired products in
good yields. Base sensitive functional groups remained intact (en-
tries 6, 7). Sterically demanding o-anisidine gave an excellent yield
(83%, entry 4) indicating the applicability of sterically hindered
amines in this transformation. Aliphatic amines were also used in

M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
4175
Table 3
Synthesis of pyridine analogs of the cardiogenols
Entry
PyeArNH
RNH2
Product
Yield (%)
O
O
H
O
H2N
1
73
64
N
H
N
N
l
N
N
N
H
C
H
O
H
6a
12a
O
O
H2N
OH
2
N
H
l
C
N
N
N
H
O
H
H
6a
12b
O
O
NH
NH
H2N
3
89
H
O
H
O
N
N
N
F
H
11a
12c
O
O
NH
NH
N
H2N
4
91
H
O
H
O
N
N
H
F
11b
12d
Reaction conditions: RNH2 (8 equiv), 150 ꢁC, 3 days, argon atmosphere.
to the BuchwaldeHartwig cross-coupling process. This result is not
unexpected according to literature reports, which stated that nu-
cleophilic substitution of fluorine in 2-position of pyridine can
occur even at rt without the presence of base.23 Hence, it is rather
remarkable that in all other cases no nucleophilic substitution of
fluorine was observed.
a subsequent SuzukieMiyaura coupling reaction. Coupling at 6-
position of pyridine is well explored24 and there is also literature
precedence for the coupling of 2-amino substituted-6-chloropyr-
idines using Pd(OAc)2 as catalyst and K3PO4 as base (three exam-
ples, yield 68%e83%).25 Consequently, we conducted the Suzuki
coupling with phenylboronic acid at 6-position utilizing Pd(PPh3)4
as catalyst and K2CO3 as base, which successfully produced the
desired product in excellent yield (96%). Attempts to combine the
Suzuki and Buchwald coupling steps in an one pot protocol were
not successful, however (Scheme 6).
2.6. Synthesis of 2,4 and 2,6-diamino substituted pyridines
In order to synthesize pyridine analogs of Cardiogenol C, a sec-
ond amination reaction had to be carried out on either 2-aryla-
mino-6-chloro- or 4-arylamino-2-fluoropyridine. For this purpose,
a nucleophilic substitution of the remaining halide was carried out
by using the aliphatic amines as solvents at high temperature
(150 ꢁC). Still, nucleophilic substitution of the halogen by aliphatic
amines on arylamino substituted pyridines was very slow and it
took 3 days to achieve complete conversion. As summarized in
Table 3, the desired products were synthesized with good to ex-
cellent yields, demonstrating the principal applicability of the
overall methodology to access pyridine analogs of cardiogenols.
Scheme 6. SuzukieMiyaura coupling on 2-aminosubstututed-6-chlopyridine.
3. Conclusions
2.7. Suzuki coupling on 2-amino substituted-6-chloropyridive
derivatives
In summary, the microwave assisted CeN cross-coupling pro-
tocol elaborated within this study is generally applicable to
a number of dihalopyridines. This enables the synthesis of valuable
building blocks for the preparation of biologically active com-
pounds and pharmaceuticals. In comparison with previous pro-
tocols the method is superior due to more facile operation
conditions (no glove box manipulation), much shorter reaction
times due to the use of a microwave reactor, as well as substantially
decreased amounts of base. The required base, K2CO3, is also very
In addition to conventional nucleophilic substitutions, the
remaining halide can also be used in CeC bond forming cross-
coupling reactions. We have already investigated the scope of the
SuzukieMiyaura reaction in 3-position of 2-amino substituted
pyridines in one of our recent publications.20 To round up our in-
vestigations on BuchwaldeHartwig products obtained within this
study, we tried to use the remaining chloride in 6-position for

4176
M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
mild, which is advantageous in case of base sensitive substrates. By
subsequently performing a nucleophilic substitution reaction of the
remaining halide with ethanol- or propanolamine a set of pyridine
analogs of the cardiogenols was obtained. Preliminary biological
screenings on these compounds to assess their cardiomyogenesis
inducing activity showed promising results in this regard.
with brine and dried over Na2SO4. Evaporating the EtOAc layer gave
the pure product.
4.4.1. 6-Chloro-N-(4-methoxyphenyl)pyridin-2-amine (6a). Prepared
according to general procedure A. Column chromatography PE/
EtOAc¼4:3. Yield: 72% (115 mg, 0.49 mmol). Appearance: yellow
solid. Mp: 74e76 ꢁC. Rf¼0.41 (PE/CH2Cl2¼4:3). GCeMS: 219 (100),
234 (Mþ, 234), 221 (32), 112 (30), 233 (27). 1H NMR (CDCl3,
4. Experimental section
4.1. General notes
200 MHz):
d
¼3.81 (s, 3H), 6.52 (d, J¼8.2 Hz, 1H), 6.65 (d, J¼7.6 Hz,
1H), 6.74 (s, 1H), 6.89 (d, J¼9.4 Hz, 2H), 7.19 (d, J¼7.2 Hz, 2H), 7.34
(t, J¼7.9 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
¼54.6 (q), 103.8 (d),
d
Unless otherwise noted, chemicals were purchased from com-
mercial suppliers and used without further purification. Microwave
reactions were performed on a CEM Explorer PLSÔ microwave unit.
Flash column chromatography was performed on silica gel 60 from
112.4 (d), 113.8 (d), 123.7 (d), 131.1 (s), 139.1 (d), 148.5 (s), 155.9 (s),
156.4 (s). Combustion analysis: requires C 61.41%, H 4.72%, N 11.94%;
found: C 61.42%, H 4.52%, N 11.78%.
Merck (40e63
m
m), whereas most separations were carried out
4.4.2. 6-Chloro-N-(4-phenoxyphenyl)pyridin-2-amine (6b). Prepared
according to general procedure A. Column chromatography 10%
EtOAc in PE. Yield: 77% (154 mg, 0.52 mmol). Appearance: yellow
crystals. Mp: 78e81 ꢁC. Rf¼0.51 (PE/EtOAc¼10:1). GCeMS: 296 (Mþ,
100), 77 (80), 295 (37), 51 (33), 298 (31). 1H NMR (CDCl3, 200 MHz):
€
using a Buchi SepacoreÔ MPLC system with a 45 g column. For thin
layer chromatography (TLC) aluminum backed silica gel was used.
Melting points were determined using a Kofler-type Leica Galen III
micro hot stage microscope and are uncorrected. HRMS were car-
ried out by E. Rosenberg at Vienna University of Technology, In-
stitute for Chemical Technologies and Analytics; all samples were
analyzed by LC-IT-TOF-MS in only positive ion detection mode with
the recording of MS and MS/MS spectra. NMR-spectra were recor-
ded in CDCl3 with TMS as internal standard or in DMSO-d6 or
CD3OD on a Bruker AC 200 (200 MHz) spectrometer and chemical
shifts are reported in parts per million. Combustional Analyses
were carried out in the Microanalytical Laboratory, Institute of
Physical Chemistry, University of Vienna. GCeMS runs were per-
formed on a Thermo Finnigan Focus GC/DSQ II using a standard
capillary column BGB 5 (30mꢂ0.32 mm ID). Either combustion
analysis or HRMS are provided for compounds not previously
reported in the literature. Characterization data of literature known
compounds are available as in the Refs. 13,20,11c.
d
¼6.58e6.75 (q, J¼7.2 Hz, 3H), 6.95e7.06 (m, 4H), 7.10 (d, J¼7.4 Hz,
1H), 7.21e7.31 (m, 3H), 7.32e7.36 (m,1H), 7.37e7.44 (m,1H).13C NMR
(CDCl3, 50 MHz):
d
¼105.3 (d), 113.9 (d), 118.5 (d), 120.0 (d), 123.2 (d),
123.6(d), 129.8 (d), 134.8 (s), 140.0 (d), 149.7 (s), 153.5 (s), 156.7 (s),
157.5 (s). Combustion analysis: requires C 68.81%, H 4.42%, N 9.44%,
found: C 68.60%, H 4.22%, N 8.92%.
4.4.3. 6-Chloro-N-[(4-morpholinyl)phenyl]pyridin-2-amine
(6c). Prepared according to general procedure A. Column chro-
matography using PE/EtOAc¼1:1. Yield: 77% (151 mg, 0.52 mmol).
Appearance: light green crystal. Mp: 140e145 ꢁC. Rf¼0.46 (PE/
EtOAc¼1:1). GCeMS: 289 (Mþ, 100), 231 (73), 230 (53), 291 (34),
232 (28). 1H NMR (CD3OD, 200 MHz):
d
¼2.92e3.20 (br s, 4H),
3.81e3.86 (m, 4H), 6.62 (t, J¼7.7 Hz, 2H), 6.95 (d, J¼8.0 Hz, 1H),
7.30e7.49 (m, 3H). 13C NMR (CD3OD, 50 MHz):
d¼54.4 (q), 64.4 (q),
4.2. General procedure A
103.8 (d), 112.4 (d), 113.8 (d), 123.9 (d), 130.9 (s), 139.1 (d), 148.5 (s),
155.9 (s), 156.4 (s). Combustion analysis: requires C 62.18%, H 5.57%,
N 14.50%, found: C 62.31%, H 5.15%, N 14.43%.
Dihalopyridine (1 equiv), amine (1.2 equiv), K2CO3 (3.5 equiv),
Pd(OAc)2 (2 mol %), and BINAP (2 mol %) were charged into a mi-
crowave vial and dry toluene was added. The vial was then sealed,
evacuated, and flushed with argon. Then the reaction mixture was
irradiated at 180 ꢁC in a CEM ExplorerÔ microwave unit for 30 min
(in few cases 45 min) with stirring. After cooling to rt, the solid
material was removed by filtration and washed with 10 mL of
EtOAc or CH2Cl2. The organic phases were combined and the sol-
vent was evaporated. The resulting crude product was purified by
flash column chromatography.
4.4.4. N1-(6-Chloropyridin-2-yl)-N4-phenylbenzene-1,4-diamine
(6d). Prepared according to general procedure A. Column chro-
matography 15% EtOAc in PE. Yield: 79% (158 mg, 0.53 mmol).
Appearance: brown oil. Rf¼0.34 (CH2Cl2). GCeMS: 295 (100), 296
(Mþ, 100), 297 (34), 167 (32), 169 (21). 1H NMR (CD3OD, 200 MHz):
d
¼6.52e6.67 (m, 2H), 6.71e6.82 (m), 6.95e7.09 (m, 4H), 7.10e7.22
(m, 2H), 7.30e7.44 (m, 3H). 13C NMR (CD3OD, 50 MHz):
d¼108.2 (d),
113.4 (d), 117.4 (d), 120.1 (d), 120.5 (d), 122.8 (d), 130.1 (d), 135.0 (s),
140.3 (s), 140.8 (d), 146.1 (s) 150.3 (s), 158.4 (s, C2). HRMS: requires
[MH]þ¼296.0954; found 296.0949.
4.3. General procedure B
Compound 6a (1 equiv) was mixed with appropriate amine
(8 equiv) and heated in a screw cap vial under argon at 150 ꢁC in
a heating block for 3 days. After cooling to rt water (5 mL)
was added and the mixture was extracted with EtOAc (5 mL) for
three times. The EtOAc layer was then washed with brine and
subsequently dried over Na2SO4. Evaporating the EtOAc layer
gave the crude product, which was purified by flash column
chromatography.
4.4.5. 6-Chloro-N-(4-chlorophenyl)pyridin-2-amine (6f). Prepared
according to general procedure A. Column chromatography 10%
EtOAc in PE. Yield: 53% (85 mg, 0.36 mmol). Appearance: orange
solid. Mp: 95e96 ꢁC. Rf¼0.38 (PE/EtOAc¼4:1). GCeMS: 237 (100),
238 (72), 239 (Mþ, 100), 168 (61), 240 (46). 1H NMR (CDCl3,
200 MHz):
d
¼6.59 (d, J¼8.2 Hz, 1H), 6.66 (d, J¼7.2 Hz, 2H), 7.19 (m,
4H), 7.33 (t, J¼7.5 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
¼106.2 (d),
d
114.6 (d), 121.9 (d), 128.4 (d), 129.3 (s), 138.2 (s), 140.1 (d), 149.7 (s),
155.7 (s). Combustion analysis: requires C 55.26%, H 3.37%, N
11.72%; found: C 55.31%, H 3.17%, N 11.43%.
4.4. General procedure C
Compound 11a/11b (1 equiv) was mixed with the appropriate
amine (8 equiv) and heated in a screw cap vial under argon at
150 ꢁC in a heating block for 3 days. After cooling to rt 2 N solution
of NaOH (5 mL) was added and the mixture was extracted with
EtOAc (15 mL) for three times. The EtOAc layer was then washed
4.4.6. N-(6-Chloropyridin-2-yl)-4-phenylthiazol-2-amine
(6k). Prepared according to general procedure A. Column chroma-
tography PE/EtOAc¼2:1. Yield: 73% (142.5 mg, 0.50 mmol). Appear-
ance: yellow solid. Mp: 167e170 ꢁC. Rf¼0.61 (PE/EtOAc¼2:1).
GCeMS: 287 (Mþ,100), 289 (39), 288 (25), 286 (21), 251 (19). 1H NMR

M. Koley et al. / Tetrahedron 67 (2011) 4169e4178
4177
(CDCl3, 200 MHz):
7.09 (s, 1H), 7.16e7.28 (m, 1H), 7.29e7.44 (m, 3H), 7.87 (d, J¼6.9 Hz,
2H). 13C NMR (CDCl3, 50 MHz):
126.2 (d), 128.0 (d), 128.8 (d), 134.4 (s), 139.5 (d), 148.4 (s), 149.2 (s),
151.1 (s), 161.2 (s). Combustion analysis: requires C 58.43%, H 3.50%, N
14.60%, S 11.14%; found: C 58.71% H 3.65%, N 14.30%, S 11.16%.
d
¼6.24 (d, J¼8.0 Hz, 1H), 6.79 (d, J¼7.4 Hz, 1H),
The vial was evacuated and back filled with argon. The reaction
mixture was heated overnight (14 h) at 150 ꢁC in the heating block.
After cooling to rt, the solid material was removed by filtration and
washed with EtOAc (10 mL). The solvent was evaporated and the
resulting crude product was purified by flash column chromatog-
raphy using DCM. Yield: 96% (119 mg, 0.43 mmol). Appearance:
yellow oil. Rf¼0.31 (DCM). GCeMS: 276(Mþ, 100), 261 (96), 275
d¼106.3 (d), 108.7 (d, C3), 115.7 (d),
4.4.7. N-(6-Chloropyridin-2-yl)-N-phenylacetamide (6l). Prepared
according to general procedure A. Column chromatography PE/
EtOAc¼1:1. Yield: 11% (18 mg, 0.07 mmol). Appearance: yellow oil.
Rf¼0.54 (PE/EtOAc¼1:1). GCeMS: 202 (100), 204 (78), 205 (41), 206
(41), 277 (21), 127 (19). 1H NMR (CDCl3, 200 MHz):
d¼3.73 (s, 3H),
6.41 (s, 1H), 6.54 (d, J¼8.4 Hz, 1H), 6.77e6.88 (m, 2H), 7.06 (d,
J¼7.4 Hz, 1H), 7.15e7.25 (m, 2H), 7.29e7.49 (m, 4H), 7.90 (dd,
J1¼7.8 Hz, J2¼1.6 Hz, 2H). 13C NMR (CDCl3, 50 MHz):
¼55.6 (q),
d
(27), 246 (Mþ, 3). 1H NMR (CDCl3, 200 MHz):
d
¼2.12 (s, 3H), 7.14 (d,
105.9 (d), 111.1 (d), 114.5 (d), 123.8 (d), 126.8 (d), 128.6 (d), 128.7 (d),
133.4 (s), 138.4 (d), 139.5 (s), 156.0 (s,),156.1 (s, C6),156.9 (s). HRMS:
requires [MH]þ¼277.1319; found 277.1319.
J¼7.8 Hz, 1H), 7.23e7.32 (m, 2H), 7.33e7.49 (m, 4H), 7.64 (t,
J¼7.7 Hz, 1H). 13C NMR (CDCl3, 50 MHz):
¼24.4 (q), 118.9 (d), 121.6
d
(d), 128.0 (d), 128.6 (d), 129.5 (d), 140.1 (d), 141.4 (s), 149.6 (s), 154.7
(s), 171.0 (s). HRMS: requires [MH]þ¼247.0638; found 247.0633.
Acknowledgements
4.4.8. 2-(6-(4-Methoxyphenylamino)pyridin-2-ylamino)ethanol
(12a). Prepared according to general procedure B. Column chro-
matography (PE/EtOAc¼3:1). Yield: 73% (153 mg, 0.59 mmol). Ap-
pearance: brown oil. Rf¼0.37 (PE/EtOAc¼3:1). 1H NMR (CDCl3,
We gratefully acknowledge financial support to this project via
AWS (Uni:Invent Project Z090391). M.K. would like to thank One-
World-Scholarship Program for providing a Ph.D. fellowship.
200 MHz):
d
¼3.35 (t, J¼4.8 Hz, 2H), 3.80 (s, 3H), 3.84 (t, J¼4.6 Hz,
Supplementary data
2H), 5.80 (d, J¼7.8 Hz, 1H), 5.92 (d, J¼9.4 Hz, 1H), 6.89 (d, J¼8.9 Hz,
2H), 7.17 (d, J¼8.2 Hz, 2H), 7.32 (t, J¼7.6 Hz, 1H). 13C NMR (CDCl3,
Experimental details and NMR-spectra of the compounds are
available as supplementary data. Supplementary data related to
this article can be found online at doi:10.1016/j.tet.2011.04.060.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
50 MHz):
d
¼45.3 (t), 55.5 (q), 61.0 (t), 94.4 (d), 114.7 (d), 125.7 (d),
131.0 (s), 143.0 (d), 153.4 (s), 154.6 (d), 157.3 (s), 177.7 (s). HRMS:
requires [MH]þ¼260.1394; found 260.1389.
4.4.9. 3-[6-(4-Methoxyphenylamino)pyridin-2-ylamino]propan-1-ol
(12b). Prepared according to general procedure B. Yield: 64%
(72 mg, 0.26 mmol). Appearance: Colorless oil. Rf¼0.40 (EtOAc). 1H
References and notes
NMR (CDCl3, 200 MHz):
d
¼1.65e1.83 (m, 2H), 3.29 (t, J¼6.3 Hz, 2H),
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d
38.8 (t), 55.5 (q), 59.2 (t), 94.1 (d), 94.7 (s), 114.6 (d), 125.3 (d), 131.6
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d
(m, 2H), 3.45 (m, 2H), 3.72 (s, 3H), 5.89 (s, 1H), 6.05 (m, 2H), 6.89 (d,
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d
¼43.8 (t), 55.2 (q), 60.7 (t), 89.3
(d), 100.8 (d), 114.4 (d), 122.9 (d), 133.9 (s), 147.4 (d), 151.9 (s), 154.9
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(12d). Prepared according to general procedure C. Yield: 91%
(55 mg, 0.17 mmol). Appearance: brown solid. Mp: 166e169 ꢁC.
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d
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6.20 (dd, J1¼6.1 Hz, J2¼2.2 Hz, 1H), 6.95 (s, 2H, ArH), 6.97e7.02 (m,
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d
90.9 (d), 102.8 (d), 119.3 (d), 121.1 (d), 124.1 (d), 124.4 (d), 130.8 (d),
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Chloro-N-(4-methoxyphenyl)pyridin-2-amine (105 mg, 0.45 mmol,
1 equiv), phenylboronic acid (82 g, 0.67 mmol, 1.5 equiv), K2CO3
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