A novel strategy for the synthesis of 2-arylpyridines using one-pot 6π-azaelectrocyclization

Article abstract of DOI:10.1016/j.tetlet.2008.05.048

A novel and useful method for the synthesis of 2-arylpyridines with a high efficiency and generality was achieved by utilizing the one-pot 6π-azaelectrocyclization followed by a base treatment. This is the first example of applying a sulfonamide to the azaelectrocyclization for efficient substituted pyridine synthesis.

Full text of DOI:10.1016/j.tetlet.2008.05.048

Tetrahedron Letters 49 (2008) 4349–4351
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel strategy for the synthesis of 2-arylpyridines using one-pot
6p-azaelectrocyclization
Toyoharu Kobayashi, Sho Hatano, Hiroshi Tsuchikawa, Shigeo Katsumura *
Department of Chemistry and Open Research Center on Organic Tool Molecules, School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and useful method for the synthesis of 2-arylpyridines with a high efficiency and generality was
achieved by utilizing the one-pot 6p-azaelectrocyclization followed by a base treatment. This is the first
example of applying a sulfonamide to the azaelectrocyclization for efficient substituted pyridine
synthesis.
Received 19 March 2008
Revised 6 May 2008
Accepted 8 May 2008
Available online 13 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Synthesis
One-pot
Azaelectrocyclization
Aromatization
Pyridine, a representative heteroaromatic ring compound, plays
a significant role in various fields. For example, there are many bio-
active pyridine compounds such as the prosthetic pyridine nucleo-
presence of a pair of C4-electron-withdrawing and C6-conjugating
substituents in azatrienes to quantitatively produce the corres-
ponding dihydropyridines in 5 min at room temperature.1
5,16
1
2
tide (NADP), pyridoxine (vitamin B6), and nicotine, and there are
also many pharmaceuticals3 and agrochemicals5 possessing a
pyridine nucleus. Thus, new construction methods for multi-
substituted pyridines are still intriguing studies.6 2-Arylpyridine
Moreover, we reported two types of one-pot pyridine syntheses
,4
16b
from aldehyde 1 (Fig. 1A).
The first one was achieved by the
reaction of 1 with hydroxylamine hydrochloride in pyridine to pro-
duce the corresponding oxime, which continuously reacted with
acetyl chloride in the same solvent to produce the corresponding
pyridine derivative. The second method utilized the Peterson olefi-
nation. Thus, aldehyde 1 was treated with lithium hexamethyldisi-
lazide to produce the unstable intermediate dihydropyridine
derivative, which was continuously treated with DDQ. Although
these are new methods of pyridine synthesis under mild conditions
utilizing 6p-azaelectrocyclization, the generality of these methods
had not been totally developed because of the relative instability of
the corresponding aldehydes. We then tried to achieve the novel
7
compounds are used not only as medicinal chemicals but also as
functional materials in supramolecular and coordination chemis-
8
tries. The representative method for the synthesis of these mole-
cules is to utilize the coupling reaction of 2-metallopyridine and an
9
10
11
12
aryl halide (e.g., Negishi, Suzuki, Stille, and Kharash coupling).
-Metallopyridine, however, is usually unstable and has a low
2
compatibility with its substituents, because it needs to be prepared
from pyridyl lithium which is highly polar and basic. Although
some alternative methods for the synthesis of 2-arylpyridine have
13
recently been reported by employing pyridine-N-oxide and the
C–H bond activation of pyridine,14 they still need to be improved
regarding the aspects of yield, efficiency, and generality. In this
Letter, we describe a highly efficient and novel synthetic method
of 2-arylpyridines using our own one-pot 6p-azaelectrocyclization.
This strategy easily enabled us to obtain 2-arylpyridines by
sequential three steps in one-pot; that is, the formation of
azatriene, azaelectrocyclization, and aromatization.
one-pot 2-arylpyridine synthesis including a sequence that
involves the coupling of three components (amine, vinylstannane,
and iodoolefin) in the presence of a palladium catalyst, generation
of dihydropyridine by 6p-azaelectrocyclization, followed by
aromatization by a treatment of base (Fig. 1B).
We first investigated the desirable amine derivative for the one-
pot reaction possessing the appropriate leaving ability (Table 1).
Acetamide and methylcarbamate did not produce the desired dihy-
dropyridine derivative under the conditions which were previously
In a previous study, we found the significant acceleration of 6p-
azaelectrocyclization by the obvious substituent effect due to the
established for our asymmetric one-pot azaelectrocyclization:17
a
mixture of amine derivative, vinylstannane, and iodoolefin in
DMF was stirred at 80 °C in the presence of a Pd catalyst, trifuryl-
phosphine, and lithium chloride (Table 1, entries 1 and 2). In the
*
Corresponding author. Tel.: +81 79 565 8314; fax: +81 79 565 9077.
E-mail address: katsumura@kwansei.ac.jp (S. Katsumura).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.048

4
350
T. Kobayashi et al. / Tetrahedron Letters 49 (2008) 4349–4351
Figure 1. (A) Previous method for one-pot pyridine synthesis via 6p-azaelectrocyclization. (B) Novel one-pot pyridine synthesis from three components.
Table 1
Investigation of the desirable amine derivative
sulfonamide, iodoolefin, and vinylstannane, which were stable and
easily synthesized.
Next, we investigated the generality of our one-pot pyridine
1
9
synthesis using various vinylstannanes in order to make this
method a practical synthetic strategy for 2-arylpyridines (Table
2). We applied two methods: Method A {Pd
2 3 3
(dba) , P(2-furyl) ,
LiCl, DMF, 80 °C then DBU, rt} shown in Scheme 1 was normally
used and method B {Pd(PhCN) Cl , LiCl, DMF, 50–70 °C then DBU,
2 2
Entry
R1-NH
MeCONH
MeOCONH
t-BuSONH
MeSO NH
2
Time (h)
Yield (%)
1
2
3
4
2
12
12
1.5
2
—
—
18
72
2
2
Table 2
2
2
One-pot pyridine synthesis using various vinyl stannanes
case of 2-methyl-2-propanesulfinamide, the desired product was
obtained in low yield (Table 1, entry 3). When methanesulfon-
amide possessing a greater electron-withdrawing property was
applied under the same condition, the reaction cleanly proceeded
to afford the corresponding dihydropyridine in 72% yield.
Entry
1
R
Condition
A
Product
Yield (%)
75
4
Next, the conversion of the obtained dihydropyridine deriva-
tives into the desired pyridine compounds was examined (Scheme
1
). After various trials, we obtained the required pyridine deriva-
2
3
4
A
B
B
8p
58
56
67
18
tive 4 in 55% yield using DBU as a base in DMF. The one-pot
transformation from methanesulfonamide 5, iodoolefin 6,
1
6b
and
1
9
vinylstannane 7 into pyridine 4 was then examined. After the
one-pot azaelectrocyclization of the three components, the result-
ing dihydropyridine was detected by TLC, and then DBU was added
and the mixture was stirred at room temperature for another 1 h.
As a result, the desired pyridine compound 4 was successfully
obtained in 75% yield. Thus, we could rapidly construct the
pyridine skeleton from the following three components: methane-
9p
10p
5
6
B
B
11p
12p
76
77
7
B
13p
49
Scheme 1. (A) Conversion of dihydropyridine 3 to pyridine 4. (B) One-pot pyridine
synthesis from three components (5, 6, and 7).
Method A: Pd
Method B: Pd(PhCN)
2
(dba)
3
, P(2-furyl)
3
, LiCI, DMF, 80 °C then DBU, rt.
2
CI , LiCI, DMF, 50–70 °C then DBU, rt.
2

T. Kobayashi et al. / Tetrahedron Letters 49 (2008) 4349–4351
4351
3.
4.
5.
6.
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MDDR: MDL Drug Data Registry, by MDL Informations Systems: San Leandro,
California, USA.
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Lett. 2008, 10, 285; (e) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
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Cross-coupling Reactions; Wiley-VCH: Weinheim, 1998.
7.
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209; (b) Roppe, J. R.; Wang, B.; Huang, D.; Tehrani, L.; Kamenecka, T.;
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1
0. For example, see: (a) Schomaker, M. J.; Delia, J. T. J. Org. Chem. 2001, 66, 7125;
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055; (b) Mathieu, J.; Gros, P.; Fort, Y. Tetrahedron Lett. 2001, 42, 1879.
(
5
Figure 2. Plausible reaction mechanism leading to pyridine derivative 4 by one-pot
azaelectrocyclization–aromatization.
1
rt} was often superior to method A.20 When the pyridine deriva-
tives of vinylstannane were used, the corresponding pyridylpyri-
dine compounds 8p and 9p were obtained in good yield
independent from their substitution pattern (Table 2, entries 2
and 3). The quinoline and thiophene derivatives also produced pyr-
idine compounds 10p and 11p in 67% and 76% yield, respectively.
Moreover, in the case of the indole derivatives, the C3-substituted
indole 12p was obtained in high yield and the C2-substituted one
12. For example, see: (a) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem.
Lett. 1979, 1447; (b) Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.; Minato,
A.; Suzuki, K. Tetrahedron 1982, 38, 3347.
1
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Am. Chem. Soc. 1992, 114, 5888.
1
1
5. (a) Tanaka, K.; Mori, H.; Fujii, S.; Itagaki, Y.; Katsumura, S. Tetrahedron Lett.
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Katsumura, S. J. Synth. Org. Chem. Jpn. 1999, 57, 876.
3p was formed in moderate yield.21 Thus, we synthesized various
1
types of 2-arylpyridines, and established a novel strategy for
the simple and rapid synthesis of 2-arylpyridines with a high
generality.
16. (a) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373; (b) Tanaka, K.; Mori, H.;
Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001, 66, 3099.
17. (a) Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka, K.; Katsumura, S. Org. Lett.
2006, 8, 3809; (b) Kobayashi, T.; Hasegawa, F.; Tanaka, K.; Katsumura, S. Org.
The plausible reaction mechanism is shown in Figure 2. When a
mixture of 5, 6, and 7 was treated with a Pd catalyst, the Stille cou-
Lett. 2006, 8, 3813.
Data for 4: IR (KBr, cm ) 3409, 2984, 1728, 1310, 1246; 1H NMR (CDCl
À1
,
pling of 6 and 7 firstly proceeded to form the dienal 14.22 Next, the
18.
3
4
00 MHz) d 8.83 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 8.05 (m, 2H), 7.78 (dd, J = 5.1,
resulting aldehyde reacted with methanesulfonamide 5 to give
imine 15, and then rapidly underwent 6p-azaelectrocyclization to
afford the dihydropyridine 3. A Pd catalyst would act as a Lewis
acid during the imine formation, because aldehyde 14 did not react
with methanesulfonamide 5 without a Pd catalyst. After the forma-
tion of 3 was ascertained by TLC, a DBU treatment facilitated the
elimination of sulfinic acid to give the desired pyridine 4. Thus,
an efficient synthetic method of 2-arylpyridines was realized. By
using a sulfonamide resin, a library synthesis of various substituted
pyridines in the solid phase is now undertaken.
13
1
.4 Hz, 1H), 7.48 (m, 3H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H);
, 100 MHz) d 165.3, 158.4, 150.4, 138.6, 138.5, 129.4, 128.8, 127.0,
21.1, 119.7, 61.8, 14.2.
C
NMR (CDCl
3
1
19. All vinylstannanes were prepared by the coupling between the corresponding
aryl halides and trans-1,2-bis(tributylstannyl)-ethene.
20. Typical procedures of one-pot pyridine synthesis. Method A: To a solution
of methanesulfonamide (75 mg, 0.788 mmol), iodoolefin (100 mg,
.394 mmol) and vinylstannane (0.788 mmol) in DMF (5 mL/mmol) were
added Pd (dba) (7 mg, 0.008 mmol), P(2-furyl) (7 mg, 0.032 mmol) and LiCl
5
6
0
2
3
3
(34 mg, 0.788 mmol) at room temperature. After the reaction mixture was
stirred at 80 °C for 2–3 h, it was cooled to room temperature, and DBU
(
0.071 ml, 0.472 mmol) was added. The resulting mixture was stirred at this
temperature for 1 h, quenched with H O, and extracted with ether. The organic
2
In conclusion, we established a novel synthetic method for 2-
arylpyridines with a high efficiency and generality. This is based
on the effective utilization of the one-pot 6p-azaelectrocyclization
followed by aromatization. To the best of our knowledge, this is a
first example of applying a sulfonamide to the azaeletrocyclization
as a nitrogen source, whose reasonable leaving ability successfully
led to the following simple conversion of the dihydropyridine into
pyridine.
layers were combined, washed with brine, dried over MgSO , filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography to afford the desired pyridine compounds. Method B: To a
solution of methanesulfonamide 5 (75 mg, 0.788 mmol), iodoolefin 6 (100 mg,
0.394 mmol) and vinylstannane (0.788 mmol) in DMF (5 mL/mmol) were
4
2
added Pd(PhCN) (15 mg, 0.039 mmol) and LiCl (34 mg, 0.788 mmol) at room
temperature. After the reaction mixture was stirred at 50–70 °C for 2–4 h, it
was cooled to room temperature, and DBU (0.071 ml, 0.472 mmol) was added.
The resulting mixture was stirred at this temperature for 1 h, quenched with
H
2
O, and extracted with ether. The organic layers were combined, washed with
brine, dried over MgSO , filtered, and concentrated in vacuo. The residue was
4
purified by silica gel column chromatography to afford the desired pyridine
Acknowledgments
compounds.
À1
2
1. Data for 13p: IR (KBr, cm ) 3434, 1721, 1372, 1175; 1H NMR (CDCl
3
, 400 MHz)
d 8.83 (dd, J = 5.0, 0.7 Hz, 1H), 8.25 (dd, J = 1.4, 0.9 Hz, 1H), 8.20 (dd, J = 8.5,
.7 Hz, 1H), 7.90 (dd, J = 5.0, 1.4 Hz, 1H), 7.66–7.69 (m, 2H), 7.49 (m, 1H), 7.44
m, 1H), 7.31–7.41 (m, 3H), 7.26 (td, J = 7.6, 0.9 Hz, 1H), 6.91 (d, J = 0.7 Hz, 1H),
This work was financially supported by a Grant-in-Aid for
Science Research on Priority Areas 16073222 from the Ministry
of Education, Culture, Sports, Science and Technology, Japan, and
JSPS (Research Fellowship for T.K.).
0
(
13
4.45 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); C NMR (CDCl
3
, 100 MHz) d
64.9, 152.4, 149.5, 140.2, 138.1, 137.4, 137.0, 133.6, 130.2, 128.7, 127.0, 125.7,
25.3, 124.5, 122.2, 121.5, 116.2, 115.7, 61.9, 14.2.
1
1
2
2. The generation of dienal 14 was confirmed by comparing with the one, which
was obtained from the Stille coupling between vinylstannane and the
References and notes
7
corresponding alcohol of 6 followed by oxidation, in a stepwise route. If the
imine formation from 6 took place prior to the Stille coupling, the dienal 14
should not be observed.
1
2
.
.
Farhanullah; Agarwal, N.; Goel, A.; Ram, V. J. J. Org. Chem. 2003, 68, 2983.
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Hall: London, 1995; p 72.