Nickel-catalyzed addition of pyridine-N-oxides across alkynes

DOI: 10.1002/anie.200703758

Source and publish data:

Angewandte Chemie - International Edition p. 8872 - 8874 (2007)

Update date:2022-08-17

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Authors:

Kanyiva, Kyalo Stephen

Nakao, Yoshiaki

Hiyama, Tamejiro

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Article abstract of DOI:10.1002/anie.200703758

(Chemical Equation Presented) An alternative to pyridine: Pyridine-N-oxides undergo direct C-H activation and add across alkynes under mild nickel catalysis to afford (E)-2-alkenylpyridine-N-oxides in modest to good yields with high selectivity. Subsequent deoxygenation and deoxygenative functionalization proceed smoothly to give a wide variety of 2-substituted pyridines. PCyp ₃ = tricyclopentylphosphine, cod = cyclooctadiene.

Full text of DOI:10.1002/anie.200703758

Communications

DOI: 10.1002/anie.200703758

Pyridine-N-Oxide Functionalization

Nickel-Catalyzed Addition of Pyridine-N-oxides across Alkynes**

Kyalo Stephen Kanyiva, Yoshiaki Nakao,* and Tamejiro Hiyama*

Dedicated to Professor Miguel Yus on the occasion of his 60th birthday

Substituted pyridines are important intermediates in the

synthesis of pharmaceuticals and functional materials. How-

ever, most of the synthetic methods require prefunctionaliza-

tion, for example by halogenation or metalation, before

subsequent coupling reactions owing to the low reactivity of

pyridine derivatives towards aromatic electrophilic substitu-

tion reactions such as the Friedel–Crafts reaction. Whereas

direct CÀH functionalization of pyridines catalyzed by a

transition-metal complex appears to be ideal, only a few

examples are available, and these require a directing group

and suffer from harsh reaction conditions or limited substrate

[

scope. On the other hand, pyridine-N-oxides have emerged

as a promising alternative for the direct CÀH functionaliza-

of the reaction mixture showed gradual formation of (Z)-3aa

during the course of the reaction. A mixture of stereoisomers

of the 2,6-dialkenylated product 3’aa was also isolated in 7%

yield.

[

tion of pyridine rings. Herein we report the nickel-catalyzed

E-selective alkenylation of pyridine-N-oxides at C2 by means

of C2ÀH activation followed by stereoselective insertion of an

alkyne under mild conditions. The resulting adducts are

readily deoxygenated to give 2-alkenylpyridines, demonstrat-

ing that the sequence of reactions provides a novel route for

C2 functionalization of pyridine derivatives.

The present conditions were applicable to a diverse range

of pyridine-N-oxides. The addition of 2-picoline-N-oxide (1b)

gave a 93:7 (E/Z) mixture of 2-alkenylated products in 67%

yield (entry 1, Table 1); analogous results were obtained with

with 3- and 4-methylpicoline-N-oxides (entries 2 and 3,

Table 1). On the other hand, no trace of the stereoisomeric

product was observed with 5-methylpicoline-N-oxide (1e),

probably owing to the steric hindrance of the 5-methyl group

(entry 4, Table 1). Whereas the ester functionality of 5-

methoxycarbonyl-2-picoline-N-oxide (1 f) was tolerated

under the present conditions and the corresponding adduct

was obtained in high yield (entry 5, Table 1), the reaction was

We have recently reported the CÀH activation of various

five-membered heteroarenes and addition reactions across

alkynes in the presence of a catalyst generated from [Ni-

(

cod) ] (cod = cyclooctadiene) and tricyclopentylphosphine

[

PCyp ) in toluene at 358C. Although the reaction con-

ditions were ineffective for addition of pyridine itself across

alkynes even at elevated temperatures, we have found that

pyridine-N-oxide (1) undergoes the desired addition reaction

exclusively at the C2 position across 4-octyne (2a) under the

same reaction conditions to give (E)-2-(4-octen-4-yl)pyridine-

sluggish with pyridine-N-oxides bearing Cl, Br, and NO

[5]

groups. Isoquinoline-N-oxide also reacted selectively at

the C1 position (entry 6, Table 1). The hydroheteroarylation

of other alkynes such as 4-methyl-2-pentyne (2b) and 4,4-

dimethyl-2-pentyne (2c) with 1b also proceeded smoothly to

give the respective adducts, in which the bulkier substituent is

trans to the pyridyl ring, in excellent regio- and stereoselec-

tivities (entries 7 and 8, Table 1). Terminal alkynes, such as 1-

octyne and phenylacetylene, failed to participate in the

reaction presumably owing to rapid oligomerization and/or

trimerization of the alkynes.

[4]

N-oxide (3aa) in 72% yield [Eq. (1)]. The product (E)-3aa

was contaminated by small amounts of the related Z isomer,

produced most probably by isomerization of the initially

formed cis adduct. We suppose this because H NMR analysis

[

*] K. S. Kanyiva, Dr. Y. Nakao, Prof. Dr. T. Hiyama

Department ofMaterial Chemistry

Graduate School ofEngineering

Kyoto University, Kyoto 615-8510 (Japan)

Fax: (+81)75-383-2445

The resulting alkenylated pyridine-N-oxides were readily

E-mail: nakao@npc05.kuic.kyoto-u.ac.jp

thiyama@npc05.kuic.kyoto-u.ac.jp

deoxygenated with PCl to provide free 2-alkenylpyridines in

excellent yields [Eq. (2)]. Furthermore, the deoxygenative

functionalizations of the adducts were successfully demon-

[

**] This work was supported financially by Grant-in-Aids for Creative

Scientific Research (No. 16GS0209) and for Scientific Research on

Priority Area “Advanced Molecular Transformations of Carbon

Resources” (No. 18037034) from MEXT. Y.N. acknowledges The

Sumitomo Foundation for support, and K.S.K acknowledges the

Honjo International Scholarship Foundation for generous financial

support.

Supporting information for this article is available on the WWW

under http://www.angewandte.org or from the author.

8872

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8872 –8874

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Angewandte

Chemie

Table 1: Nickel-catalyzed addition ofpyridine- N-oxides across alkynes.

A plausible mechanism for this hydroheteroarylation

reaction is shown in Scheme 1. We consider that the alkyne-

[8]

coordinated nickel(0) species A undergoes oxidative addi-

[

9,10]

tion to the C2ÀH bond,

giving the pyridyl(hydride)nickel

[

[b]

Entry

t [h] Prod., Yield , E/Z

Scheme 1. A plausible mechanism for the nickel-catalyzed hydrohetero-

arylation ofalkynes using pyridine- N-oxides. The steric bulk ofR is the

same as or greater than that ofR .

1 f

species B. Hydronickelation in a cis fashion then provides the

alkenyl(pyridyl)nickel intermediate C. Coordination of the

alkyne such that the steric repulsion between the bulkier R

and the pyridyl group in B is avoided would be responsible for

the observed regioselectivities (entries 7 and 8, Table 1).

Reductive elimination followed by coordination of an alkyne

affords 2-alkenylpyridine-N-oxide 3 and regenerates the

nickel(0) species A. The N-oxide moiety plays an important

role in directing the metal catalyst to the proximal C2ÀH

bond and/or making the CÀH bond acidic enough to undergo

the oxidative addition to nickel(0).

In summary, we have demonstrated nickel-catalyzed

activation of C2ÀH bonds of pyridine-N-oxides under mild

conditions followed by regio- and stereoselective insertion of

alkynes to afford (E)-2-alkenylpyridine-N-oxides in modest

to good yields. The resulting adducts are readily deoxygen-

ated to give various substituted pyridines, which are useful

intermediates for pharmaceuticals and materials. Current

efforts are directed to further development of direct CÀH

[a] Yield ofisolated product based on 1. [b] Estimated by H NMR

spectroscopy. [c] (E,E)-1,3-Di(4-octen-4-yl)isoquinoline-N-oxide (3’ga)

was also isolated in 5% yield.

functionalization reactions under the newly disclosed nickel

catalysis under mild conditions.

strated by the reaction of 3aa with allyl(trimethyl)silane in

the presence of a catalytic amount of nBu NF to afford 5 in

[6]

1% yield [Eq. (3)] and by the transfer of the oxygen moiety Experimental Section

of 3ba to the benzylic position, affording 6 in 81% yield

General procedure: A pyridine-N-oxide (1.0 mmol) and an alkyne

[

(

¹^.⁵^m^m^o^l⁾^w^e^r^e^a^d^d^e^d^s^e^q^u^eⁿ^tⁱ^a^l^l^y^t^o^a^s^o^l^u^tⁱ^oⁿ^o^f^[^Nⁱ⁽^c^o^d⁾2^]

[

Eq. (4)].

28 mg, 0.10 mmol) and PCyp₃(24 mg, 0.10 mmol) in toluene

2.5 mL) in a dry box. The vial was taken outside the dry box and

heated at 358Cfor the time specified in Table 1. The resulting mixture

was filtered through a pad of silica gel, concentrated in vacuo, and

purified by flash chromatography on silica gel to give the correspond-

ing hydroheteroarylation products in the yields listed in Table 1.

Received: August 16, 2007

Keywords: alkynes · CÀC coupling · CÀH activation · nickel ·

pyridine-N-oxides

Angew. Chem. Int. Ed. 2007, 46, 8872 –8874

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

8873

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Communications

[

7] M. van den Heuvel, T. A. van den Berg, R. M. Kellogg, C. T.

[

1] a) R. F. Jordan, D. F. Taylor, J. Am. Chem. Soc. 1989 , 111 , 778;

Choma, B. L. Feringa, J. Org. Chem. 2004, 69, 250.

b) E. J. Moore, W. R. Pretzer, T. J. OꢀConnell, J. Harris, L.

LaBounty, L. Chou, S. S. Grimmer, J. Am. Chem. Soc. 1992 , 114 ,

[8] S. Ogoshi, M. Ueta, M. Oka, H. Kurosawa, Chem. Commun.

2004 , 2732, and Ref. [3].

[9] For an example of the oxidative addition, see: J. A. Pool, B. L.

Scott, J. L. Kiplinger, J. Am. Chem. Soc. 2005 , 127 , 1338.

[10] For examples of CÀH activation by stoichiometric and catalytic

5888; c) R. Grigg, V. Savic, Tetrahedron Lett. 1997 , 38 , 5737;

d) M. Murakami, S. Hori, J. Am. Chem. Soc. 2003 , 125 , 4720 ;

e) J. C. Lewis, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.

2007 , 129 , 5332.

amounts of nickel complexes, see Refs. [3], [7], and a) J. P.

Kleiman, M. Dubeck, J. Am. Chem. Soc. 1963 , 85 , 1544 ; b) T.

Tsuda, T. Kiyoi, T. Saegusa, J. Org. Chem. 1990 , 55 , 2554 ;

c) N. M. Brunkan, D. M. Brestensky, W. D. Jones, J. Am. Chem.

Soc. 2004 , 126 , 3627; d) N. D. Clement, K. J. Cavell, C. Jones,

C. J. Elsevier, Angew. Chem. 2004, 116, 1297; Angew. Chem. Int.

Ed. 2004 , 43 , 1277 ; e) N. D. Clement, K. J. Cavell, Angew. Chem.

2004 , 116 , 3933; Angew. Chem. Int. Ed. 2004 , 43 , 3845; f) A. L.

Keen, S. A. Johnson, J. Am. Chem. Soc. 2006 , 128 , 1806 ; g) A. L.

Keen, M. Doster, S. A. Johnson, J. Am. Chem. Soc. 2007 , 129 ,

810.

[

2] a) L.-C. Campeau, S. Rousseaux, K. Fagnou, J. Am. Chem. Soc.

2005 , 127 , 18020 ; b) J.-P. Leclerc, K. Fagnou, Angew. Chem. 2006 ,

118 , 7945; Angew. Chem. Int. Ed. 2006 , 45 , 7781.

3] a) Y. Nakao, K. S. Kanyiva, S. Oda, T. Hiyama, J. Am. Chem.

Soc. 2006 , 128 , 8146; b) K. S. Kanyiva, Y. Nakao, T. Hiyama,

Heterocycles 2007, 72, 677.

4] When less catalyst was used (1–5 mol%), 3aa was obtained in

lower yields (37–55% by H NMR spectroscopy) even after 24 h.

[

5] These pyridine-N-oxides were sparingly soluble in toluene.

6] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1983 , 24 , 889.

8874 www.angewandte.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8872 –8874

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Article Doi

Nickel-catalyzed addition of pyridine-N-oxides across alkynes

DOI: 10.1002/anie.200703758

Source and publish data:

Authors:

Article abstract of DOI:10.1002/anie.200703758

Full text of DOI:10.1002/anie.200703758

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