Regioselective syntheses of 2,3-substituted pyridines by orthogonal cross-coupling strategies

Article abstract of DOI:10.1002/ejoc.201001583

2-Aryl/alkylamino-3-aryl I and 3-aryl/alkylamino-2-aryl pyridines II, as important potentially bioactive compounds, were synthesized by applying orthogonal cross-coupling strategies. Combinations of the Suzuki-Miyaura, Liebeskind-Srogl, and Buchwald-Hartwig protocols gave access to the title compounds in a straightforward and operationally simple manner. Full control over the regioselectivity at the 2- and 3-positions was achieved by using 2,3-dichloropyridine or 3-iodo-2-(methylthio)pyridine as simple, commercially available starting materials. Within this contribution, efficient and high yielding conditions were developed for the Suzuki-Miyaura cross-coupling reaction of 2-substituted 3-chloropyridines, a transformation formerly underrepresented in the literature. For the synthesis of 3-alkyl/arylamino-2- aryl pyridines, the stability of the methylthio group was exploited under Pd-catalysis in the absence of a copper source. This even enabled the development of an operationally highly facile (semi)-one-pot protocol to access the aforementioned compound class that avoided one purification step. A series of products I and II was prepared by using the developed protocols with excellent regioselectivity and good yields. Copyright

Full text of DOI:10.1002/ejoc.201001583

FULL PAPER
DOI: 10.1002/ejoc.201001583
Regioselective Syntheses of 2,3-Substituted Pyridines by Orthogonal Cross-
Coupling Strategies
Moumita Koley,[a] Laurin Wimmer,[a] Michael Schnürch,*[a] and Marko D. Mihovilovic[a]
Keywords: Nitrogen heterocycles / Amination / Copper / Palladium / Cross-coupling / Regioselectivity
2-Aryl/alkylamino-3-aryl I and 3-aryl/alkylamino-2-aryl pyr-
idines II, as important potentially bioactive compounds, were
synthesized by applying orthogonal cross-coupling strate-
gies. Combinations of the Suzuki–Miyaura, Liebeskind–
Srogl, and Buchwald–Hartwig protocols gave access to the
title compounds in a straightforward and operationally sim-
ple manner. Full control over the regioselectivity at the 2-
and 3-positions was achieved by using 2,3-dichloropyridine
or 3-iodo-2-(methylthio)pyridine as simple, commercially
available starting materials. Within this contribution, efficient
and high yielding conditions were developed for the Suzuki–
Miyaura cross-coupling reaction of 2-substituted 3-chloro-
pyridines, a transformation formerly underrepresented in the
literature. For the synthesis of 3-alkyl/arylamino-2-aryl pyr-
idines, the stability of the methylthio group was exploited
under Pd-catalysis in the absence of a copper source. This
even enabled the development of an operationally highly
facile (semi)-one-pot protocol to access the aforementioned
compound class that avoided one purification step. A series
of products I and II was prepared by using the developed
protocols with excellent regioselectivity and good yields.
the formed product is deactivated towards a second metal-
catalyzed C–N coupling. On the other hand, combinations
of C–C and C–N coupling reactions on pyridine are rela-
tively rare, even though compounds prepared by such reac-
tions are highly likely to display biological activity. The
present study focuses on a synthetic strategy to obtain 2-
amino(aryl/alkyl)-3-aryl (I) and 2-aryl-3-amino(aryl/alkyl)
(II) substituted pyridines (Figure 1) by applying orthogonal
cross-coupling strategies. This approach should broaden the
spectrum of available reactions for the synthesis of these
types of compound, which is significant because the struc-
tural motif of substances of general structures I and II can
be found in many bioactive compounds.[8,9]
Introduction
The pyridine nucleus is regarded as a privileged hetero-
aromatic ring system due to its presence in numerous natu-
ral products and biologically active substances.[1] In the
context of medicinal chemistry, decoration of the pyridine
nucleus is, hence, an important research area. In particular,
transition metal catalyzed cross-coupling reactions repre-
sent an important and efficient method[2] in this regard.
Such processes have often been applied to pyridine, and the
regioselectivity of coupling events has been established.[3]
Although many contributions to this field have already
been published, a large number of problems remain un-
solved. Especially, overcoming the intrinsic reactivity pat-
terns in pyridine (and other heterocyclic ring systems) to
access unusual substitution patterns is often quite challeng-
ing because the synthesis of substitution patterns comple-
mentary to the usual regioselectivity is still underrepre-
sented in the literature,[4] and detailed studies are urgently
required in this regard. Carbon–carbon bond-forming cou-
pling reactions of dihalopyridines have been reported in re-
cent years and, in some cases, good selectivity was ob-
tained.[5] Similarly, C–N bond formation through Buch-
wald–Hartwig amination have also been reported for di-
halopyridines.[6,7] Here, selectivity is not an issue since usu-
ally only one amination reaction can be carried out because
Figure 1. General target structures.
We have investigated the well-established Suzuki–
Miyaura[10] and Buchwald–Hartwig[11] reactions in combi-
nation with the more recently developed Liebeskind–Srogl
(LS) method.[12] The latter reaction offers a major advan-
tage because it is orthogonal to the former two protocols.
Thioalkyl groups (e.g., SMe), which are typically used as
leaving groups in LS reactions under the influence of cop-
per(I)-thiophen-2-carboxylic acid (CuTC), are inert under
standard transition metal catalyzed cross-coupling condi-
tions (commonly conducted in the presence of base and in
[a] Vienna University of Technology,
Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax: +43-1-58801-915440
E-mail: mschnuerch@ioc.tuwien.ac.at
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001583.
1972
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1972–1979

Regioselective Syntheses of 2,3-Substituted Pyridines
the absence of a copper species). Interestingly, this orthogo- Table 1. Buchwald–Hartwig amination of 2,3-dichloropyridine.
nality has only been rarely exploited.[13] Combinations of
Suzuki–Miyaura, Stille, and Sonogashira reactions were re-
ported to take place with usually good selectivity for the
different coupling protocols. However, in the reported ex-
amples, the halide and the R–S group were either on two
different ring systems[13a,13b] or in a para-relationship.[13c]
Furthermore, examples of non-aromatic systems have been
reported.[13d,13e] These examples demonstrated that, in prin-
cipal, this transformation is extremely useful for the elabo-
ration of scaffolds with substitution patterns complemen-
tary to those obtained by using standard cross-coupling re-
actions. In our example, the two positions to be cross-cou-
pled are immediately adjacent (ortho) to each other, which
is a situation that has not, to the best of our knowledge,
been investigated previously with aromatic systems. Poten-
tially, this could also allow for a one-pot protocol in which
the LS reaction is combined with a second cross-coupling
reaction. Our investigations in this direction are reported
here.
Results and Discussion
The synthesis of target compounds I (Figure 1) was car-
ried out in two stages. Palladium-catalyzed amination was
performed in the 2-position as the first step in the reaction
sequence (Table 1). This transformation, which was inde-
pendently discovered by Buchwald and Hartwig,[11,14] has
been applied successfully in the synthesis of aryl or alkyl
amino substituted pyridines.[15] However, only a few exam-
ples of amination reactions on dihalogenated pyridines have
been reported in the literature that use either palladium[6]
or nickel catalysts.[6c,7] Most relevant for this contribution,
C–N bond formation took place selectively at the 2-position
in 2,3-dichloropyridine. Although selective, this protocol
leaves much room for improvement because of the need for
[a] The reaction was carried out at 150 °C under conventional heat-
20 equiv. of base (K2CO3) and rather long reaction times
ing.
(ca. 18 h in toluene at reflux).[6b] The large amount of base
used in this protocol proved to be necessary to drive the
reaction to completion, a phenomenon already previously
encountered in amination reactions.[16] The authors stated
Simple aniline (Table 1, entry 1) as well as anilines carry-
that attempts to decrease the amount to 5 or 10 equiv. ing electron-donating (Table 1, entry 2) or electron-with-
K2CO3 resulted in incomplete conversion.[6b] Because this drawing (Table 1, entries 3 and 4) substituents in the para
large amount of base makes this transformation unpractical position were well-tolerated, and good yields were ob-
and uneconomical, even though a relatively inexpensive tained. Additionally, all regioisomeric pyridinamines (o-, m-,
base is applied, we first screened for conditions to circum- and p-) were introduced (Table 1, entries 5–7) without sig-
vent this problem. After some optimization, we found that nificant differences in yield, demonstrating that heterocyclic
simply carrying out the reaction under microwave irradia- amines are also applicable. Interestingly, alkylamines gave
tion (180 °C) not only shortened the reaction time dramati- generally lower yields. Benzylamine, as a representative of
cally to 30–45 min, but also allowed the amount of base a primary alkylamine, was obtained in only 52% (Table 1,
to be decreased to only 3.5 equiv. (Table 1). Lowering the entry 8). Secondary alkylamines performed slightly better
amount of base even further gave lower conversions and (Table 1, entries 9 and 10), however, secondary amines
isolated yields. This protocol proved to be very versatile and proved to be sufficiently nucleophilic to also participate in
generally applicable, and a series of 3-chloro-2-arylamino- non-catalytic nucleophilic substitution reactions. In a con-
pyridines was prepared (Table 1).
trol experiment with piperidine in toluene in a screw-cap
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M. Schnürch et al.
FULL PAPER
vial at 180 °C, the product was obtained in 45% yield, how- der palladium catalysis conditions. It has been reported that
ever, under these conditions, the reaction was not complete 2-phenylpyridines can be arylated in the 2-position of the
even after 24h. Because the yield and reaction rate are sig- phenyl ring through the formation of a favorable five-mem-
nificantly higher in the presence of palladium (45 vs. 62%), bered metallacycle.[20] However, in this case, a six-mem-
it can be concluded that cross-coupling and nucleophilic bered metallacycle has to be formed for direct arylation.
substitution mechanisms operate simultaneously when ali- Here, much less precedence can be found in the litera-
phatic amines are used as reaction partners, with the metal- ture;[21] although 1,2,3,4-tetrahydro-1-(2-pyridinyl)quin-
catalyzed amination being the faster process. In the case of oline was arylated in position 8 using a rhodium catalyst,
arylamines, a control experiment showed that no conver- to the best of our knowledge, no palladium-catalyzed
sion was observed in the absence of palladium catalyst.
The aryl substituent in the 3-position was then intro-
duced by applying a Suzuki–Miyaura cross-coupling reac-
tion. Although the applicability of aryl chlorides as sub-
strates was established in recent years,[17] coupling at the 3-
position of chloropyridines has not been studied extensively
and only very few examples have been reported in the litera-
ture.[18] To the best of our knowledge, there are no literature
examples concerning Suzuki–Miyaura couplings with 3-
chloro-2-amino-substituted pyridines and even examples
with other substituents in the 2-position are rare.[19] Hence,
a literature protocol for the preparation of 3-phenylpyridine
from 3-chloropyridine was used as starting point for our
optimization efforts. Most importantly, the influence of dif-
ferent ligands and different bases was studied.[18e] As ex-
pected, the use of bulky Buchwald-type ligands proved to
be mandatory to obtain good conversion. However, in con-
trast to the previous literature report,[18e] cross-coupling at
room temperature was not possible, and conducting the re-
action at 150 °C proved to be necessary. Regarding the cata-
lyst, use of 2-dicyclohexylphosphanyl-2Ј,4Ј,6Ј-triisopro-
pylbiphenyl (DCPTPB) gave the best results, again in com-
bination with K2CO3 as base, which was superior to both
KF and K3PO4 (see the Supporting Information for details
on the optimization). The reaction of various phenyl bor-
onic acids with different 2-(aryl/alkyl)amino-3-chloropyr-
idines gave excellent yields of the desired products, which
were, in most cases, independent of the nature of the amine
in the 2-position (Table 2). For example, phenylboronic acid
and (4-methoxyphenyl)boronic acid were introduced into
the 3-position of 2a in 92 and 91% yield, respectively
(Table 2, entries 1 and 2). 3-Nitrophenylboronic acid gave a
lower yield of 67% (Table 2, entry 3). Coupling of 2b, 2e,
2f, and 2g with phenylboronic acid gave excellent results in
all cases (Table 2, entries 6–9). A lower yield of product 3i
was obtained in the presence of piperidine as a sterically
more demanding substituent in the 2-position (60%;
Table 2, entry 10). Cross-coupling reaction with sterically
demanding o-tolylboronic acid represented a special case;
with this substrate, two different products were formed
(Table 2, entries 4 and 5, compounds 3d and 4) that had the
same mass according to GC–MS and HRMS analysis. The
expected product 3d was formed in 28%, accompanied by
the formation of byproduct 4 in 23% yield. The structure
of 4 was elucidated by 2D NMR spectroscopic methods
(see the Supporting Information). To confirm this result,
the reaction was repeated several times and 4 was always
formed in varying amounts. Formation of this product can
be explained by an unexpected CH-activation pathway un-
method has been reported.
Table 2. Suzuki–Miyaura coupling of compounds 2.
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Regioselective Syntheses of 2,3-Substituted Pyridines
Finally, an attempt was made to combine the two reac- acted to give 2-methylthio-3-phenylpyridine. In fact, the
tion steps into a one-pot protocol by simply adding the pyridine starting material itself is a sufficiently strong base
phenylboronic acid to the reaction mixture after the amin- to facilitate the Suzuki–Miyaura reaction. The addition of
ation step. A series of different conditions was tested (see 2 equiv. of zinc acetate, which was used to mask bases[12c]
the Supporting Information), but the model compound 3a in the LS reaction, did not change the outcome of the reac-
could never be obtained in more than 34% yield (58% per tion.
individual step), which is clearly lower than the stepwise
protocol (64% overall, 71% in the amination and 92% in
the C–C cross-coupling step). Details of the optimization
of the one-pot protocol are summarized in the Supporting
Information.
Next, a protocol to synthesize the isomeric 2-aryl 3-aryl/
Scheme 1. Synthesis of compounds II: (a) amine (1.2 equiv.),
Cs2CO3 (2.5 equiv.), Pd(OAc)2 (0.05 equiv.), BINAP (0.05 equiv.),
130 °C, anhydrous toluene; (b) boronic acid (1.5 equiv.), CuTC
(1.4 equiv.), [Pd(PPh3)4] (0.05 equiv.), 50 °C, toluene/THF (1:1).
alkylamino compounds II was developed. Although 2,3-
dichloropyridine or 2,3-dibromopyridine are conveniently
accessible and/or commercially available, these precursors
were not selected as substrates for several reasons. Clearly,
the C–C bond-forming step has to be carried out first, be-
cause this would preferably take place in the 2-position,
thus Suzuki–Miyaura coupling reactions of 2,3-dibromopyr-
idine were investigated.[5b,22] In one contribution, high, but
not complete, selectivity (95–99%) for the monoarylated
over the bisarylated product was achieved in the coupling
reaction with electron-rich boronic acids.[22] No conclusions
were made concerning the applicability of electron-poor re-
action partners or further cross-coupling in the 3-position.
In the other example,[5b] a double-Suzuki one-pot protocol
was reported that gave yields ranging from 28–86%, but
no detailed discussion of the selectivity of the process was
reported. Besides one example involving the use of p-
AcC6H4-B(OH)2 as the aryl donor for coupling in the 3-
position, only electron-rich donors were applied.[5b]
Furthermore, subsequent C–N coupling in the 3-position is
problematic. Palladium-catalyzed aminations of 3-chloro-
pyridines have been described, but, in these cases, either ali-
phatic amines were employed exclusively as coupling part-
ners[23] or the use of very elaborate ligands was required.[24]
Switching to 3-bromo-2-chloropyridine as starting material
and initiating the sequence with the C–N bond forming step
was also not a promising strategy because competitive nu-
cleophilic substitution of the chlorine in the 2-position was
very likely to occur.[25] Therefore, including an inert substit-
For the first step in the reaction sequence – Buchwald–
Hartwig coupling with aryl/alkylamines[11] in the 3-posi-
tion
– optimized conditions were quickly identified
(Table 3) and a series of aryl/alkylamines was successfully
introduced to explore the substrate scope. Electron-de-
ficient anilines required longer reaction times, as could be
expected (Table 3, entries 2 and 3), whereas aniline and 4-
methoxy aniline reacted much faster (Table 3, entries 1 and
4).
Table 3. Buchwald–Hartwig amination of 5.
Subsequently, isolated 6a was reacted in an LS coupling
uent in the 2-position should offer an appealing approach under standard conditions[12c] to explore the feasibility of
to circumvent selectivity problems and obtain 2,3-function- the overall reaction sequence (Scheme 2). This reaction gave
alized target compounds II, exclusively. To this end, 3-iodo- 84% yield of 7a after 24 h (an overall yield of 57% over
2-(methylthio)pyridine (5), which was prepared from 2-fluo- two steps). To establish a one-pot protocol, in an initial
ropyridine in two simple steps, was selected as starting ma- experiment, we simply added CuTC and phenylboronic acid
terial (see the Supporting Information). This substrate is to the reaction mixture of the amination step. However, no
especially suitable for our purpose because the more acti- conversion of 6a into 7a was observed. When additional
vated 2-position is blocked by the methylthio group and, [Pd(PPh3)4] was added, 21% of 7a was formed after 24 h.
hence, the amination reaction takes place exclusively in the This demonstrated that base remaining from the first step
3-position (Scheme 1). In a unique strategy, the methylthio inhibited the reaction. To remove the base, CH2Cl2 was
group, which is not reactive under conventional coupling added to decrease the solubility of Cs2CO3 and the reaction
conditions, can then be activated and the 2-position can be mixture was filtered through Celite before the solvent was
coupled in an LS reaction.[12] In theory, a reversal of the evaporated. By using this protocol, a series of products (7a–
coupling events (i.e., first LS, then Buchwald–Hartwig cou- e and 7g–h) could be obtained in 59 to 79% yield over both
pling) could be feasible because, under base-free conditions, reaction steps. It is important to emphasize that this corre-
the iodine in the 3-position might be stable. However, when sponds to good to excellent yields (75–90%) for the two
this approach was tested, only the iodine in 3-position re- individual steps (Table 3, entries 1–8, yields in parenthesis).
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M. Schnürch et al.
FULL PAPER
In the case of p-nitroaniline (Table 3, entry 4) a significantly Table 4. (Semi)-one-pot LS reaction of 5.
longer reaction time of 72 h was required for the first cou-
pling step, compared to 3–4.5 h in all other cases. When
the LS reaction was carried out with o-tolylboronic acid, a
significantly lower yield was obtained, most likely due to
steric hindrance (Table 3, entry 6).
Scheme 2. Synthesis of 7a from purified 6a.
Although the procedure described above was already a
simplification of the stepwise protocol with purification of
intermediate 6, further improvement was envisioned by
either avoiding intermediate filtration or solvent evapora-
tion. It was previously shown that removal of the base is
essential. In contrast, evaporation of the solvent would not
be necessary if one solvent could be used for both reaction
steps. To find a solvent suitable for both reaction steps, a
solvent screening was performed. Tetrahydrofuran (THF)
and toluene were selected because these solvents have al-
ready been used in either one of the reaction steps (toluene
for the amination, THF for the LS coupling). The use of
THF (b.p. 66 °C) in the first reaction step, however, would
require high pressure at the required reaction temperature
of 130 °C. Consequently, dioxane, which has a higher boil-
ing point, was considered as an alternative to THF.
Furthermore, the application of solvent mixtures was also
investigated. Optimal results were obtained when anhy-
drous THF was added to give a 1:1 mixture with toluene
(for optimization reactions see Supporting Information).
In the final protocol the toluene solution of the amin-
ation reaction was simply filtered through a pad of Celite
and then diluted with the same amount of THF before ad-
dition of boronic acid (1.5 equiv.), CuTC (1.4 equiv.), and
[Pd(PPh3)4] (0.05 equiv.). The results are summarized in
Table 4. It has to be emphasized that yields given in Table 4
are combined yields of both reaction steps. For comparison,
compound 7a was obtained in 71% yield in the sequential
protocol compared to only 57% when intermediate 6a was
isolated. This demonstrates that, in terms of yield, the pro-
tocol without purification is superior to the alternative ap-
proach involving isolation of the intermediate; the com-
bined one-pot approach is also more efficient with respect
to time and waste because one purification step can be avo-
ided.
[a] Prepared according to general protocol D. [b] Prepared accord-
ing to general protocol E.
plained by a very limited stability of this particular boronic
acid.
Steric hindrance turned out to be problematic in the LS
reaction step. A low yield of 7f (31%) was obtained with o-
tolylboronic acid and no reaction occurred at all with very
bulky amines in the 3-position. For example, piperidine
underwent the Buchwald–Hartwig reaction, but the amine
formed was unreactive in the subsequent LS reaction. Simi-
larly, 7e was obtained in only 40% yield; in this case, the
CH2 group seems to impart some increased steric demand.
Comparing the two developed protocols for (semi)-one-
pot reactions, there is no clear trend in terms of higher
yields. In our hands, the second variant (involving the
mixed toluene/THF solvent system) seems favorable as it is
more operationally simple.
Conclusions
Both electron-rich and electron-poor aryl donors were
accepted, as summarized in Table 4. Compounds 7a–c, 7g,
Microwave-assisted C–N cross-coupling reactions with
and 7h were obtained in yields ranging from 54 to 76%, 2,3-dichloropyridine, followed by Suzuki–Miyaura coupling
which corresponds to 73–87% calculated yields for the indi- reaction, gave 2-aryl/alkyamino-3-aryl-substituted pyridines
vidual steps. A lower yield of 40% was achieved for com- I in good yields. Synthesis of the isomeric 2-aryl-3-alkyl/
pounds 7d and 7e. The coupling reaction with furan bor- arylamino substituted pyridines II was also successfully ac-
onic acid gave compound 7i in only 33%; this can be ex- complished, this time even in a (semi)-one-pot protocol
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Regioselective Syntheses of 2,3-Substituted Pyridines
H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 115.1 (d), 119.3
(d), 121.9 (d), 123.7 (s), 128.2 (d), 128.9 (d), 129.1 (d), 129.4 (d),
137.5 (s), 137.8 (d), 140.6 (s), 146.9 (d), 152.7 (s) ppm. HRMS: m/z
[MH]+ calcd. 247.1230; found 247.1236 (diff. 2.43 ppm).
starting from 3-iodo-2-(methylthio)pyridine by applying
Buchwald–Hartwig and subsequent Liebeskind–Srogl cou-
pling reactions. This sequence demonstrates that orthogo-
nal conditions can be applied to cross-coupling methods,
and these can be efficiently exploited in synthetic sequences
to obtain isomeric compounds that are otherwise difficult
to prepare by more conventional routes.
General Procedure C: Substrate 5 (1.0 equiv.), amine (1.2 equiv.),
Pd(OAc)2 (5 mol-%), BINAP (5 mol-%), and anhydrous Cs2CO3
(2.5 equiv.) were placed in an oven-dried 6 mL-vial with septum
screw-cap and a magnetic stirring bar. The vial was evacuated and
flushed with argon (three cycles) and anhydrous toluene (1–2 mL)
was added through the septum to give an approximate 0.2 m solu-
tion of the pyridine derivative. Under a flow of argon, the cap with
septum was quickly exchanged for a closed cap (because caps with
septum tended to leak when the vial was set under pressure). The
reaction mixture was heated to 130 °C in a heating block. To take
samples, the reaction mixture was cooled to room temp. and the
vial was opened. After taking the sample, the vial was flushed with
argon and closed. The reaction was monitored by TLC and/or GC–
MS and stopped when complete consumption of the starting mate-
rial was observed. The reaction mixture was cooled to room temp.,
filtered through Celite and the solvents evaporated. The desired,
pure product was obtained after MPLC using the solvent mixture
indicated for TLC (45–90 g, SiO2). Compounds 6a–d were prepared
according to this procedure.
Experimental Section
General Procedure A: 2,3-Dichloropyridine (1 equiv.), amine
(1.2 equiv.), K2CO3 (3.5 equiv.), Pd(OAc)2 (2 mol-%), and BINAP
(2 mol-%) were charged into a microwave vial and anhydrous tolu-
ene was added. The vial was then sealed, evacuated, and flushed
with argon. Then the reaction mixture was irradiated at 180 °C in
a CEM Explorer™ microwave unit for 30 min (in a few cases for
45 min) with stirring. After cooling to room temp., the solid mate-
rial was removed by filtration and washed with CH2Cl2 (10 mL).
The combined organic layers were evaporated and the resulting
crude product was purified by flash column chromatography. Com-
pounds 2a–j were prepared according to this procedure.
3-Chloro-N-phenylpyridin-2-amine (2a): The reaction was carried
out according to general procedure A with 2,3-dichloropyridine
(150 mg, 1.01 mmol, 1 equiv.), aniline (114 mg, 1.22 mmol,
1.2 equiv.), K2CO3 (491 mg, 3.55 mmol, 3.5 equiv.), Pd(OAc)2
(5 mg, 0.020 mmol, 2 mol-%), and BINAP (12 mg, 0.020 mmol,
2 mol-%) in anhydrous toluene (2.5 mL). The product was purified
by flash column chromatography (light petroleum/EtOAc, 5:1) to
give the pure product 2a as a yellow oil (71%, 195 mg, 0.95 mmol).
GC–MS: m/z (%) = 203 (100), 204 (45), 205 (42) [M+], 207 (52),
2-(Methylthio)-N-phenylpyridin-3-amine (6a): Prepared according
to procedure C (reaction time: 3 h) with 5 (50 mg, 0.2 mmol) and
aniline (22 mg, 0.24 mmol) to give the product (69%, 0.14 mmol,
30 mg) as a light-brown oil. Rf = 0.52 (light petroleum/EtOAc, 2:1).
1H NMR (CDCl3, 200 MHz): δ = 2.54 (s, 3 H), 5.52 (br. s, 1 H),
3
3
6.85 (dd, JH,H = 8.0, JH,H = 4.7 Hz, 1 H), 6.87–6.97 (m, 3 H),
3
4
7.17–7.25 (m, 2 H), 7.33 (dd, JH,H = 8.0, JH,H = 1.4 Hz, 1 H),
8.03 (dd, 3JH,H = 4.7, 4JH,H = 1.4 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 13.4 (q), 119.0 (d), 119.8 (d), 121.8 (d), 122.2 (d),
129.6 (d), 137.6 (s), 141.8 (s), 141.9 (s), 148.9 (s) ppm. GC–MS:
m/z (%) = 216 (100) [M+], 183 (82), 182 (51), 181 (44), 169 (37).
HRMS: m/z [M + H]+ calcd. 217.0794; found 217.0786 (diff.
–3.69 ppm).
1
3
168 (21). H NMR (200 MHz, CDCl3, 25 °C): δ = 6.71 (dd, JH,H
4
3
= 7.8, JH,H = 2.9 Hz, 1 H), 6.98 (s, 1 H), 7.06 (t, JH,H = 7.3 Hz,
3
3
4
1 H), 7.35 (t, JH,H = 7.5 Hz, 1 H), 7.57 (dd, JH,H = 7.6, JH,H
=
3
3
1.6 Hz, 1 H), 7.63 (d, JH,H = 8.0 Hz, 2 H), 8.13 (dd, JH,H = 4.9,
4JH,H = 1.6 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ
= 115.2 (d), 116.1 (s), 119.9 (d), 122.8 (d), 128.9 (d), 136.7 (d),
139.6 (s), 145.8 (d), 151.3 (s) ppm.
General Procedure D: For the Buchwald–Hartwig reaction, com-
pound 5 (1.0 equiv.), amine (1.2 equiv.), Pd(OAc)2 (5 mol-%), BI-
NAP (5 mol-%), and anhydrous Cs2CO3 (2.5 equiv.) were placed in
an oven-dried 6 mL-vial fitted with a septum screw-cap and a mag-
netic stirring bar. The vial was evacuated and flushed with argon
(three cycles). Anhydrous toluene (1–2 mL) was added through the
septum to give an approximate 0.2 m solution of the pyridine deriv-
ative. Under a flow of argon, the cap with septum was quickly
exchanged for a closed cap and the reaction mixture was heated to
130 °C in a heating block. To take samples, the reaction mixture
was cooled to room temp. and the vial was opened. After taking
the sample, the vial was flushed with argon and closed. The reac-
tion was monitored by TLC and/or GC–MS and stopped when
complete consumption of the starting material was observed. The
reaction mixture was cooled to room temp., diluted with CH2Cl2,
filtered through Celite, evaporated, and re-dissolved in anhydrous
THF (1–2 mL) under argon.
General Procedure B: Pyridin-2-amine derivative 2 from the above
protocol (1 equiv.), the corresponding boronic acid (3 equiv.),
K2CO3 (2 equiv.), Pd(OAc)2 (1 mol-%), and DCPTPB (2 mol-%) in
anhydrous toluene (2 mL) were charged into a screw-cap vial. The
vial was evacuated and re-filled with anhydrous argon and the reac-
tion mixture was heated overnight (14 h) at 150 °C. After cooling
to room temp., the solid material was removed by filtration and
washed with EtOAc (10 mL). The combined solvents were evapo-
rated and the resulting crude product was purified by flash column
chromatography using a suitable solvent mixture. Compounds 3a–
i and 4 were prepared according to this procedure.
N,3-Diphenylpyridin-2-amine (3a): The reaction was carried out ac-
cording to general procedure B with 3-chloro-2-(phenylamino)pyr-
idine (53 mg, 0.26 mmol, 1 equiv.), phenylboronic acid (97 mg,
0.79 mmol, 3 equiv.), K2CO3 (72 mg, 0.52 mmol, 2 equiv.),
Pd(OAc)2 (0.6 mg, 0.003 mmol, 1 mol-%), and DCPTPB (2.5 mg,
0.005 mmol, 2 mol-%) in anhydrous toluene (2 mL). The product
For the LS reaction, boronic acid (1.3–1.5 equiv.), copper(I)-thio-
phene-2-carboxylate (1.4 equiv.), and [Pd(PPh3)4] (5 mol-%) were
was purified by flash column chromatography (EtOAc/light petro- placed in an oven-dried 6 mL-vial with septum screw-cap and a
leum, 10%) to give the pure product 3a as a yellow oil (92%, 59 mg,
magnetic stirring bar. The vial was evacuated and flushed with ar-
0.24 mmol). GC–MS: m/z (%) = 245 (100), 246 (39) [M+], 121 (29), gon (three cycles). The solution of intermediate 6 was added
1
115 (24), 77 (22). H NMR (200 MHz, CDCl3, 25 °C): δ = 6.51 (s,
through the septum to give an approximate 0.2 m solution of the
pyridine derivative. The reaction was monitored by TLC and/or
GC–MS and stopped either when complete consumption of the
intermediate was observed or when no further significant change
3
4
3
1 H), 6.82 (dd, JH,H = 7.3, JH,H = 5.1 Hz, 1 H), 6.96 (t, JH,H
=
3
7.3 Hz, 1 H), 7.20–7.32 (m, 2 H), 7.34 (d, JH,H = 1.9 Hz, 1 H),
7.39–7.55 (m, 7 H), 8.23 (dd, JH,H = 4.9, JH,H = 1.9 Hz, 1
3
4
Eur. J. Org. Chem. 2011, 1972–1979
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1977

M. Schnürch et al.
FULL PAPER
was seen. The reaction mixture was cooled to room temp., filtered
through Celite, and the solvents evaporated. The desired, pure
product was obtained after MPLC applying the solvent mixture
indicated for TLC (45–90 g, SiO2).
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(5 mol-%), and anhydrous Cs2CO3 (2.5 equiv.) were placed in an
oven-dried 6 mL-vial with septum screw-cap and a magnetic stir-
ring bar. The vial was evacuated and flushed with argon (three
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tum to give an approximate 0.2 m solution of the pyridine deriva-
tive. Under a flow of argon, the cap with septum was quickly ex-
changed for a closed cap. The reaction mixture was heated to
130 °C in a heating block. To take samples, the reaction mixture
was cooled to room temp. and the vial was opened. After taking
the sample, the vial was flushed with argon and closed. The reac-
tion was monitored by TLC and/or GC–MS and stopped when
complete consumption of the starting material was observed. The
reaction mixture was cooled to room temp. and quickly filtered
through Celite. The removed solid was washed with toluene
(0.5 mL) and the organic layers containing intermediate 6 were
combined.
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For the LS reaction, boronic acid (1.3–1.5 equiv.), copper(I)-thio-
phene-2-carboxylate (1.4 equiv.), and [Pd(PPh3)4] (5 mol-%) were
placed in an oven-dried 6 mL-vial with septum screw-cap and a
magnetic stirring bar. The vial was evacuated and flushed with ar-
gon (three cycles). The filtered reaction solution of intermediate 6
obtained as described above was then added through the septum
and the same amount of THF was added. The reaction was heated
to 50 °C, monitored by TLC and/or GC–MS, and stopped either
when complete consumption of the intermediate was observed, or
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was cooled to room temp., filtered through Celite, and the solvents
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N,2-Diphenylpyridin-3-amine (7a): Prepared according to procedure
E for 3 h/24 h at 130 °C/50 °C with anhydrous toluene then toluene/
THF (1:1) as solvent, compound 5 (100 mg, 0.4 mmol), aniline
(44 mg, 0.48 mmol), and phenylboronic acid (73 mg, 0.6 mmol) to
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=
3
8.3, JH,H = 4.6 Hz, 1 H), 7.17–7.25 (m, 2 H), 7.33–7.44 (m, 3 H),
7.55–7.63 (m, 3 H), 8.19 (d, JH,H = 4.1 Hz, 1 H) ppm. 13C NMR
3
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(50 MHz, CDCl3, 25 °C): δ = 119.1 (d), 122.4 (d), 122.9 (d), 124.1
(d), 128.8 (d), 128.9 (d), 129.1 (d), 129.7 (d), 137.5 (s), 137.9 (s),
141.6 (d), 142.0 (s), 148.3 (s) ppm. GC–MS: m/z (%) = 247 (14),
246 (89) [M+], 245 (100), 115 (9), 77 (14). HRMS: m/z [M + H]+
calcd. 247.1230; found 247.1229 (diff. –0.04 ppm).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, optimization efforts, and analytical
data.
Acknowledgments
This work received financial support by the Austrian Wirtschafts-
service (AWS), Uni:Invent Project Z090391. M. K. would like to
thank the Afro-Asiatisches Institut (AAI) for providing a fellow-
ship under the One-World Scholarship program.
1978
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: November 24, 2010
Published Online: February 23, 2011
Eur. J. Org. Chem. 2011, 1972–1979
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1979