Library-directed solution-And solid-phase synthesis of 2,4-disubstituted pyridines: one-pot approach through 6π-azaelectrocyclization

Article abstract of DOI:10.1002/asia.200900146

An efficient one-pot synthetic procedure for the synthesis of 2,4-disubstituted pyridines has been successfully established. The method proceeds through a 6π-azaelectrocyclization-aromatization sequence. Using this method, a wide variety of pyridine struc

Full text of DOI:10.1002/asia.200900146

DOI: 10.1002/asia.200900146
Library-directed Solution- and Solid-phase Synthesis of 2,4-Disubstituted
Pyridines: One-pot Approach through 6p-Azaelectrocyclization
Taku Sakaguchi,[a] Toyoharu Kobayashi,[a] Sho Hatano,[a] Hiroshi Tsuchikawa,[a]
Koichi Fukase,[b] Katsunori Tanaka,*[b] and Shigeo Katsumura*[a]
Abstract: An efficient one-pot synthetic procedure for the synthesis of 2,4-disubsti-
tuted pyridines has been successfully established. The method proceeds through a
6p-azaelectrocyclization-aromatization sequence. Using this method, a wide varie-
ty of pyridine structures substituted at the 2-position have been rapidly construct-
ed from vinyl stannanes, vinyl iodide, sulfonamide, and a palladium catalyst. The
method was further applied to the solid-phase synthesis wherein the use of a
“traceless” sulfonamide linker enabled the rapid preparation of a small library of
pyridines with high purity, without any chromatographic separation.
Keywords: cross-coupling · electro-
cyclic reactions · nitrogen heterocy-
cles · solid-phase synthesis · sulfo-
namides
Introduction
dines have been synthesized by coupling 2-metallopyridine
with an aryl halide or alkylation with the pyridine N-
oxides.[7] Improved methods for the substitution at the 2-po-
sition of the pyridine ring have recently been reported,
Substituted pyridines play a significant role in various fields
such as biology, pharmacology, and medicinal chemistry.
There are many bioactive pyridines such as the prosthetic
pyridine nucleotide (NADP)[1] and nicotine.[2] A pyridine
nucleus can also be found in many pharmaceuticals[3,4] as
well as agrochemicals.[5] Pyridine derivatives are applied to
synthetic organic chemistry as well. For example, dimethyla-
minopyridine (DMAP) is a powerful nucleophilic base,
often used for carboxylic acid activation and acylation. Con-
sidering the importance of pyridines, especially the substitut-
ed pyridines, a large number of synthetic methods have
been developed, and they are still one of the most intriguing
topics in the synthetic community.[6] Traditionally, 2-arylpyri-
À
which uses transition metal-catalyzed variants, such as C H
bond activation of the C1-hydrogen of pyridines through the
coordination of the nitrogen to ruthenium,[8a–d] rhodium,[8e]
or a nickel/Lewis acid complex.[8f] Alternatively, the ring-
closing metathesis (RCM)-aromatization sequence,[9a] the
three-component coupling between alkoxyallene, nitrile, and
carboxylic acid,[9b] the condensation of N-vinyl and N-aryl
amides to p-nucleophiles,[9c] and the ring expansion of isoxa-
soles[9d] have also been used to construct 2-substituted pyri-
dines. Although these methods have proved to be quite
useful for the preparation of these important heterocycles,
they still need to be further improved in terms of efficiency,
generality, and simplicity of the procedure.
[a] T. Sakaguchi, Dr. T. Kobayashi, S. Hatano, Dr. H. Tsuchikawa,
Prof. Dr. S. Katsumura
The heteroatom-substituted electrocyclic reaction is
widely utilized in organic synthesis, such as pentannula-
Department of Chemistry and Open Research Center on Organic
Tool Molecules
School of Science and Technology
Kwansei Gakuin University
Gakuen 2-1, Sanda, Hyogo 669-1337 (Japan)
Fax : (+81)79-565-9077
E-mail: katsumura@kwansei.ac.jp
AHCTUNGTRENNUNG
tion,[10a] 2H-pyran synthesis,[10b] and dihydropyridine synthe-
sis.[10c] Especially, 6p-azaelectrocyclization of 1-azatrienes is
quite an attractive candidate for the construction of substi-
tuted pyridine skeletons, because the dihydropyridine, as a
cyclized product, can easily be transformed to the corre-
sponding pyridine, either by oxidative or eliminative aroma-
tization. Nevertheless, the application of electrocyclization
protocol to the substituted pyridine synthesis has been limit-
ed because of the difficulty in handling the unstable precur-
sor, 1-azatrienes, under the vigorous reaction conditions re-
quired for electrocyclization. The tedious synthesis of the
[b] Prof. Dr. K. Fukase, Dr. K. Tanaka
Department of Chemistry
Graduate School of Science
Osaka University
1-1 Machikaneyama, Toyonaka, Osaka 560-0043 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900146.
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FULL PAPERS
variously substituted 1-azatrienes, for diversification of the
pyridine substituents, also limits the general application. Re-
cently, the application of metal-catalyzed protocols and/or
the in situ generation of 1-azatrienes has overcome the in-
stability problem of the azatriene precursor; thus, the elec-
trocyclization strategy in the substituted pyridine synthesis
has now been refocused. For instance, Trost and co-workers
prepared the 1-azatriene from diynols using a ruthenium
catalyst.[11a] Rhodium catalysts were also applied to synthe-
size the 1-azatrienes, either from a,b-unsaturated benzyl
imines and alkynes[11b] or from a,b-unsaturated ketoximes
and alkynes.[11c] Liebeskind and co-workers have reported
the Cu-catalyzed cross coupling of alkenyl boronic acids
with oximes to yield the 3-azatrienes.[11d] Now, useful aza-
electrocyclization has been developed for the synthesis of
natural products. Weinreb and co-workers achieved the total
synthesis of Ageladine A and its analogues using 6p-aza-
electrocyclization.[12]
Scheme 1. Rapid 6p-azaelectrocyclization by substituent effects.
tion-aromatization sequence in detail.[17] The method is
quite general for the substituents at the 2-position of the
pyridines, and a variety of aromatic- and olefin-containing
pyridines were rapidly constructed using the substituted
vinyl stannanes, vinyl iodide, sulfonamides, and a palladium
catalyst (see Scheme 2 and Table 1). In pursuit of the li-
brary-directed synthesis of the substituted pyridines, the re-
We have recently achieved a significant acceleration of
the 6p-azaelectrocyclization by the substituent effects be-
cause of the presence of a pair of C4-electron withdrawing
and C6-conjugating groups in azatriene systems (Scheme 1).
The reaction quantitatively produces the corresponding 1,2-
dihydropyridines in 5 min at room temperature.[13–16] Based
on these findings, we have reported two types of one-pot
procedures for the synthesis of 2,4-substituted pyridines
from the unsaturated aldehydes
Scheme 2. One-pot pyridine synthesis by azaelectrocyclization.
1.[14b] The first method involves
the azaelectrocyclization of the
oxime derivative (R1 =OAc)
followed by dehydrative aroma-
tization. The second method
makes use of the aza-Peterson
olefination of 1 with lithium
bis(trimethylsilyl)amide (R1 =
TMS) and the oxidative aroma-
tization of the resulting N-
TMS-substituted dihydropyri-
dine. Although our azaelectro-
cyclization strategy can be per-
formed under extremely mild
conditions in comparison with
the previously reported proto-
cols, the generality of the meth-
ods has not been totally realiz-
ed in terms of the substituent
diversity at the 2-position on
the pyridines; it is rather diffi-
cult to synthesize the unsaturat-
ed (E,E)-ester aldehyde 1 by
the introduction of a variety of
substituents at the 5-position
(Scheme 1).
Table 1. Solution- and solid-phase synthesis of substituted pyridines.
entry
R
product solution-
phase
solid-
phase
entry
R
product solution-
phase
solid-
phase
yield [%][a] yield [%][c]
yield [%][a] yield [%][c]
1
6a
6b
90
76
6
7
6 f
6g
77
49
69
31
2
3
4
58[b]
40[d]
6c
6d
6e
56
67
76
76
8
6h
6i
54
75
52[d]
78
9
13
22[d]
31
5
10
6j
60[b]
We herein report an efficient
one-pot procedure for the syn-
thesis of substituted pyridines
[a] Pd
(20 mol%), P
U
2ACHTUNGTRENNUNG(dba)3
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
through a 6p-azaelectrocycliza- then DBU (1.0 eq), THF, RT, 1 h.
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Chem. Asian J. 2009, 4, 1573 – 1577

One-pot Synthesis of Disubstituted Pyridines
action was also performed on solid-supports in which the
use of a “traceless” sulfonamide linker enabled the rapid
preparation of the small library of pyridines with high
purity.
derivatives 2 f and 2g, because of the stannyl substitution at
the 2- and 3-positions of the indole. Although the 2-(3-indo-
lyl)pyridine 6 f was obtained in 77% (entry 6), the 2-(2-indo-
lyl)pyridine 6g was produced in moderate yield (49%,
entry 7). Similarly, 2-(2-naphthyl)pyridine (6h) was pro-
duced in 54% (entry 8), but the furyl derivative 6i was ob-
tained in only 13% yield by the current one-pot synthesis
(entry 9). Not only the aromatic-substituted pyridines, but
also the alkenyl substituted congener 6j could also be pre-
pared in 60% yield by applying the stannane 2j (entry 10).
An efficient and general one-pot protocol for the C2-substi-
tuted pyridine derivatives was thus established.
The method was further applied to the library-directed
synthesis of the substituted pyridines on solid-supports. The
application of the solid-supported technology will signifi-
cantly simplify the purification procedures and will provide
the desired products after cleavage from the resin.[20] We en-
visioned that the pyridines could efficiently be prepared on
the solid-supports by the application of the sulfonamide
linker as the traceless linker (Scheme 3). The multi-compo-
Results and Discussion
We have already achieved one-pot chiral piperidine synthe-
sis[18] using aryl substituted vinyl stannanes such as 2a, vinyl
iodide 3 (Scheme 2), chiral substituted cis-1,2-aminoinda-
nols[19] and a palladium catalyst, and the same method was
directly applied to the current pyridine synthesis. The appli-
cation of an amine with an appropriate leaving group such
as methanesulfonamide (MeSO2NH2) 4 might achieve the
À
efficient elimination of H SO2Me from the 1,2-dihydropyri-
dines such as 5 in the base treatments (Scheme 2). We ini-
tially examined amides suitable for the one-pot dihydropyri-
dine formation; a DMF solution of styryl stannane 2a, vinyl
iodide 3, and amides were heated to 808C in the presence of
a Pd2ACHTUNGTRENNUNG(dba)3/PACHTUNGTRENNUNG(2-furyl)3 catalyst, according to the already es-
tablished protocol for piperidine synthesis (Scheme 2).[18] Al-
though acetamide and methylcarbamide did not provide any
detectable dihydropyridine for 12 h, methanesulfonamide 4
gave the corresponding N-sulfonyl dihydropyridine in 72%
within 2 h. As we expected, when the dihydropyridine 5 was
subsequently treated with DBU in DMF at room tempera-
ture, the desired pyridine 6a was obtained in 55% yield
(Scheme 2).
Having proved the concept of the pyridine synthesis
through a multiple sequence of reactions, namely, the Stille
coupling–Schiff base formation–azaelectrocyclization–elimi-
nation pathway (vide infra), the whole procedure was opti-
mized to be realized in the same flask (one-pot procedure).
After the dihydropyridine formation was detected by TLC,
DBU was directly added to the same flask. Gratifyingly, by
this simplified procedure, the pyridine 6a was obtained in
75% yield.
The most prominent feature of the one-pot procedure is
that differently substituted pyridines at the C2-position can
easily be accessed by various vinyl stannanes (Table 1). The
vinyl stannanes 2a–2j with various aromatics or olefins,
which can be easily prepared by the hydrostannylation of
the corresponding acetylenes, were applied to the current
one-pot synthesis. Most of the entries in Table 1 were exam-
Scheme 3. Substituted pyridine synthesis on solid-supports.
nent synthesis of dihydropyridine on the solid-supports fol-
lowed by DBU treatment would provide the desired pyri-
dines with the concomitant release from the solid-supports.
The product could then be separated from the DBU, simply
by an extraction operation.
Thus, following the procedure established for the solu-
tion-phase reaction, a DMF solution of styryl stannane 2a,
vinyl iodide 3, PdACHTNUGTRNEG(UN PhCN)2Cl2, and LiCl was shaken with the
sulfamylbutyryl AM resin (Novabiochem) at 808C for 2 h.
After the excess reagents were removed by washing sequen-
tially with DMF, diethyl ether, and THF, the resulting dihy-
dropyridine-bound resin was treated with DBU in THF at
room temperature for 1 h. After the resulting solution was
washed with a saturated ammonium chloride solution, the
product was extracted to an ethyl acetate phase. By such a
simple operation, the desired pyridine 6a was obtained in
76% yield with high purity as judged from the 1H NMR
spectrum (Figure 1).
Based on the solid-phase procedure established above, a
variety of the 2,4-disubstituted pyridines 6a–6j could be ef-
ficiently and rapidly accessed as shown in Table 1. Except
for a few cases, such as entries 7 and 10, the solid-supported
protocol provided the corresponding pyridines in the com-
ined using Pd
was found to show a reactivity superior to that of Pd
(2-furyl)3, previously utilized as shown in Scheme 2. Under
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
P
ACHTUNGTRENNUNG
the optimized conditions, the simple styryl stannane 2a pro-
vided the C2-phenyl substituted pyridine 6a in 90% yield
(entry 1). The pyridine-substituted stannanes 2b and 2c also
gave the corresponding pyridines 6b and 6c in good yields,
independent of their substitution positions (58% and 56%,
entries 2 and 3). The quinoline- and the thiophene-substitut-
ed stannanes 2d and 2e similarly produced 6d and 6e in
67% and 76% yields, respectively (entries 4 and 5). A slight
difference in reactivity was observed for the indolyl stannyl
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K. Tanaka, S. Katsumura et al.
FULL PAPERS
tion in this laboratory. Finally, the DBU treatment then pro-
motes the elimination of sulfinic acid from the dihydropyri-
dine 9 to provide the pyridine derivatives.
Conclusions
In summary, we have established a one-pot synthesis of 2,4-
disubstituted pyridines from easily available materials
through the multi-step sequences of the reactions, namely,
Stille coupling, Schiff base formation, azaelectrocyclization,
and aromatization. Because variously substituted vinyl stan-
nanes as one component of the reacting materials can easily
be accessed from the corresponding acetylenes, the present
method offers a quite general strategy for the synthesis of
2,4-disubstituted pyridines. Moreover, the protocol was ap-
plied to solid-supported synthesis by using the sulfonamide
linker as a “traceless linker”, which further expanded the
applicability of the method, that is, to the library-directed
combinatorial synthesis. To the best of our knowledge, this
is the first example in which the azaelectrocyclic reaction
was applied to solid-phase synthesis. Further application of
the methods to the highly substituted pyridines, as well as
the combinatorial synthesis/screening of the substituted pyri-
dines with the promising biological activity, is now in prog-
ress in these laboratories.
Figure 1. 1H NMR spectrum of 6a after extraction operation.
parable yields to those obtained by the solution-phase pro-
cedure. Notably these substituted pyridines were obtained in
their pure forms without any chromatographic separation,
thus expanding the methods to the library-directed combina-
torial synthesis of the substituted pyridines.
The plausible mechanism for this one-pot pyridine synthe-
sis is shown in Scheme 4. Initially, the dienal 7 was obtained
as the Stille coupling product, which was detected in the re-
Experimental Section
Representative procedure of method a
(solution-phase, PdACHTNUTRGNEUNG(PhCN)2Cl2) for
the synthesis of 2-phenyl-4-ethoxycar-
bonylpyridine (6a). Reagents of Pd-
AHCTUNGTERG(NNUN PhCN)2Cl2 (15 mg, 0.039 mmol) and
LiCl (34 mg, 0.79 mmol) were added
to a solution of methane sulfonamide
(75 mg, 0.79 mmol), vinyl iodide
3
(100 mg, 0.39 mmol), and vinyl stan-
nane 2a (310 mg, 0.788 mmol) in DMF
at room temperature. The mixture was
then stirred at 508C for 20 min. After
the mixture was cooled to room tem-
perature, DBU (0.071 mL, 0.47 mmol)
Scheme 4. Plausible mechanism of the one-pot pyridine synthesis.
was added. The resulting mixture was
stirred at this temperature for 1 h,
quenched with H2O, and extracted
action mixture. The aldehyde 7 subsequently reacts with the
sulfonamide to produce the corresponding 1-azatriene 8,
which underwent smooth 6p-azaelectrocyclization to pro-
vide the dihydropyridine 9. Because the cyclization of 8 is a
very fast process, the success of the whole process depends
on the Schiff base formation of 7 with a weak nucleophilic
sulfonamide. Interestingly, in this reaction, the palladium
catalyst might facilitate such a process, because the aldehyde
7, which was independently prepared from 2a and 3 by the
Stille coupling, did not react with methanesulfonamide 4
without a Pd catalyst. Furthermore, we found that iodotribu-
tylstannane, a byproduct of the Stille coupling, is essential
for the success of the Schiff base formation/electrocycliza-
tion process in Scheme 4, which is currently under investiga-
with ether. The organic layers were combined, washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo to give the crude prod-
ucts. Column chromatography on silica gel (from 9% to 17% ethyl ace-
tate in hexane) gave the pyridine product 6a (81 mg, 90%) as yellow
crystals: m.p.: 40.5–42.08C; IR (KBr disk): n˜ =3409, 2984, 1728, 1310,
1246 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.83 (d, J=5.1 Hz, 1H), 8.30
;
(s, 1H), 8.05 (m, 2H, J=7.1 Hz), 7.78 (dd, 1H, J=5.1, 1.4 Hz), 7.48 (m,
3H), 4.45 (q, 2H, J=7.1 Hz), 1.44 ppm (t, 3H, J=7.1 Hz); 13C NMR
(100 MHz, CDCl3): d=165.3, 158.4, 150.4, 138.6, 138.5, 129.4, 128.8,
127.0, 121.1, 119.7, 61.8, 14.2 ppm; ESI HRMS: m/z (%) calcd for
C14H13NO2: 228.1025 [M+H]+; found: 228.1030.
Representative procedure of method b (solution-phase, Pd2ACTHNUTRGNNEG(U dba)3, PACHTUNGTRENNUNG(2-
furyl)3) for the synthesis of 6a. To a solution of methane sulfonamide
(75 mg, 0.79 mmol), vinyl iodide 3 (100 mg, 0.39 mmol), and vinyl stan-
nane 2a (310 mg, 0.79 mmol) in DMF were added Pd
2ACHTUNGTRENN(UNG dba)3 (7 mg,
0.008 mmol), (2-furyl)3 (7 mg, 0.032 mmol), and LiCl (34 mg,
PACHTUNGTRENNUNG
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Chem. Asian J. 2009, 4, 1573 – 1577

One-pot Synthesis of Disubstituted Pyridines
0.79 mmol) at room temperature. The mixture was then stirred at 808C
for 2 h. After the mixture was cooled to room temperature, DBU
(0.071 mL, 0.47 mmol) was added. The resulting mixture was stirred at
this temperature for 1 h, quenched with H2O, and extracted with ether.
The organic layers were combined, washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo to give the crude products.
Column chromatography on silica gel (from 9% to 17% ethyl acetate in
hexane) gave the pyridine product 6a (90 mg, 75%) as yellow crystals.
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Representative procedure of the solid-phase synthesis of 6a. Sulfamylbu-
tyryl AM resin (100 mg, 0.11 mmol) was washed with DMF twice. To the
washed resin, a DMF solution of vinyl iodide 3 (56 mg, 0.22 mmol), vinyl
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stannane 2a (173 mg, 0.44 mmol), PdACHTNUGTRNEUNG(PhCN)2Cl2 (8 mg, 0.022 mmol), and
LiCl (11 mg, 0.26 mmol) was added at room temperature, and the result-
ing mixture was shaken at 808C for 2 h. The solution was then washed
off, and the resin was washed sequentially with DMF, ether (each 2 mL,
5 sets), and then THF. To the obtained resin, a THF solution of DBU
(0.05 mL, 0.33 mmol) was added, and the resulting mixture was shaken at
room temperature for 1 h. The solution was washed off, and the resin
was washed with THF and ether (each 2 mL, 5 sets). The resulting THF
and ether solutions were combined, washed with sat. NH4Cl aq. and
brine, dried over MgSO4, filtered, and concentrated in vacuo to give the
pyridine product 6a (19 mg, 76%) as yellow crystals.
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Acknowledgements
This work was financially supported by a Grant-in-Aid for Science Re-
search on Priority Areas (16073222) from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan. This work was also support-
ed by the Matching Fund Subsidy for Private University of Japan. T.K. is
grateful to the JSPS for a Research Fellowship for Young Scientist.
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