钯催化吡啶氮氧化物C-H活化

Published on Web 06/27/2008

Palladium-Catalyzed C -H Functionalization of Pyridine N -Oxides:Highly Selective Alkenylation and Direct Arylation with Unactivated Arenes

Seung Hwan Cho, Seung Jun Hwang, and Sukbok Chang*

Department of Chemistry and School of Molecular Science (BK21),Korea Ad V anced Institute of Science and

Technology (KAIST),Daejon 305-701, Republic of Korea

Received April 10, 2008; E-mail:[email protected]

Transition metal-catalyzed C -H bond functionalization for the C -C bond formation has emerged as a promising area in organic synthesis. 1In particular, reactions involving Pd-catalyzed activation of sp 2or sp 3C -H bonds of arenes or alkanes have been extensively investigated. 2Successful applications of the C -H activation strategy on readily available substrates have been also reported using various metals other than Pd catalysts. 3,4

Pyridine moiety is a key component of pharmacophores, natural products, and synthetic building blocks. 5Substituted pyridines are usually prepared starting from halo-or metallated pyridyl com-pounds. However, this “prefunctionalization ”route is inevitably accompanied with problems such as the need of extra preparation steps for the frequently unstable precursors and the formation of byproducts. Inspired by the key contributions from Fagnou 6a–dand Hiyama group, 6e we envisioned that the C -H bond activation approach using pyridine N -oxides would serve as an attractive platform for the 2-functionalization of pyridine species. 7Described herein are two new protocols for the oxidative C -C bond formation of pyridine N -oxides; selective alkenylation and direct cross-coupling with unactivated arenes.

At the outset on the alkenylation of N -oxides based on the Fujiwara -Moritani approach, 8we tried to optimize the reaction conditions using pyridine N -oxide (1a ) and ethyl acrylate (Table1). 9It was found that the nature of oxidants, additives, and solvent play a critical role on the reaction efficiency.While no reaction took place without oxidants and additives in acidic solvent (entry1), the addition of AgF (3.0equiv) produced noticeable yield that was further increased in 1,4-dioxane alone (entries2and 3). We subsequently found that the addition of certain bases provided more significantimprovement (entry5). Finally, the reaction proceeded highly efficientlywhen 10mol %of Pd(OAc)2was used in combination with Ag 2CO 3(1.5equiv) and pyridine (1.0equiv, entry 8). 10This transformation is highly site-selecti V e at the 2-position and no regioisomeric products of 3a were observed. In addition, it proceeds with complete stereoselectivity to generate (E )-3a exclu-sively. Moreover, the chemoseletivity was remarkably high since it did not suffer from double alkenylation at all.

As shown in Scheme 1, a palladium complex (A ) bound to the N -oxide oxygen was isolated by the treatment of 1a with PdCl 2(PPh3) 2which showed a moderate catalytic activity giving 3a in 66%yield under the optimized conditions. 9When A was submitted to various reaction conditions with 2a , no alkenylated product 3a was obtained, suggesting that the N -oxide-bound Pd complex A is probably a resting species positioned outside the catalytic cycle. In fact, Hiyama proposed that the C -H activation of pyridine N -oxides 6e or their equivalents 7d proceeds via the direct oxidative addition of Ni(0)center to the acidic C2-H bond. On the other hand, Kiplinger suggested that N -oxide-bound actinide species serve as distinct precursors for the subsequent ortho C -H bond activation of bound pyridine N -oxide. 11

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Table 1. Optimization for the Alkenylation of Pyridine N -Oxide

a

entry oxidant (equiv)solvent additive yield (%)b

1none

AcOH/1,4-dioxanec none

none 55AgF (3.0)1,4-dioxane K 2CO 3546Ag 2O (1.5)1,4-dioxane K 2CO 3607Ag 2CO 3(1.5)1,4-dioxane K 2CO 3728

Ag 2CO 3(1.5)1,4-dioxane pyridine 96(91)

a

Conditions:1a (4equiv), ethyl acrylate (0.3mmol), Pd(OAc)2(10mol %),oxidant (1.5∼3.0equiv), additive (1.0equiv), and solvent (0.6mL) at 100°C for 12h. b NMR yield (isolatedyield in parenthesis). c

Volume ratio of 1:3(AcOH/1,4-dioxane).

Scheme 1. Preparation and Molecular Structure of a Complex

A

Kinetic isotope competition experiments were also carried out under the reaction conditions to reveal the intermolecular kinetic isotope effects (k H/D) being 2.9(eq1). 12In addition, when proto-(1a ) and deutero-(1a-d 5) substrates were run side by side in separate flasks,a significantrate difference was observed. 9

The scope of the alkenylation reaction was broad as shown in Table 2. Olefinsconjugated with ester, amide, or ketone groups were all smoothly alkenylated at the 2-position of 1a (entries1-3). Diethyl vinylphosphonate also participated in the reaction (entry4). We were pleased to observe that aliphatic olefinswere readily reacted with 1a in modest yield (entry5). Moreover, (E )-2-styrylpyridine N -oxide was efficientlyobtained by the reaction with styrene at higher temperatures (entry6).

Pyridine N -oxides substituted with a phenyl group at the para or ortho position were readily alkenylated with satisfactory yields (entries7and 8). Interestingly, 3-phenylpyridine N -oxide underwent the alkenylation with excellent selectivity at the less bulky site (entry9). Furthermore, other types of N -oxides derived from pyrazine,

10.1021/ja8026295CCC:$40.75 2008American Chemical Society

C O M M U N I C A T I O N S

Table 2. Highly Selective Alkenylation of Various N -Oxides a

b

Reaction conditions:olefin(0.3mmol), N -oxide (4equiv), Pd(OAc)2(10mol %),Ag 2CO 3(1.5equiv) in 1,4-dioxane (0.6mL) at 100°C for 12h. Isolated yield. c At 120°C for 16h.

Table 3. Pd-Catalyzed Direct Arylation of Various N -Oxides Using Unactivated Arenes

a

a

Reaction

conditions:N -oxide (0.6mmol), Pd(OAc)2(10mol %),Ag 2CO 3(2.2equiv), and arene (40equiv) at 130°C for 16h. b Isolated yield of product mixture. c Ratio of isolated products. d Run using 2equiv of Ag 2CO 3. e PdCl 2(dppe)(10mol %)was used. f Run using 1equiv of Ag 2CO 3.

a

quinoxaline, and pyridazine were also viable substrates for the ortho alkenylation reactions (entries10-12).

The resultant alkenylated pyridine N -oxides (e.g.,3a ) were readily deoxygenated to give 2-alkenylpyridines (eq2), 6e making the present alkenylation route a highly attractive alternative for the 2-functionalization of pyridine derivatives. 7,13

During the course of our studies on the alkenylation reaction, we observed that 2-phenylpyridine N -oxide (4a ) was produced as a side product in addition to the desired alkenylated compound (3a ) when the reaction was carried out in benzene at 130°C (eq3). Obviously, the ortho arylated product 4a can be envisioned to generate oxidatively by the cross-coupling of simultaneously activated species of pyridine N -oxide and benzene by Pd catalyst. Although a few reports have described the oxidative cross-coupling of (hetero)arylspecies with arenes via the double C -H bond activation route, 14convenient arylation of certain heteroaro-J. AM. CHEM. SOC.

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matics such as pyridine still remains as a challenge to work with. This consideration made us to search for optimal conditions for the arylation of pyridine N -oxides with simple arenes since this approach was envisioned to serve as an efficientalternative way for the direct arylation of pyridines.

Among various conditions screened using 1a and benzene, 9we optimized the oxidative arylation of N -oxides as follows:arenes (40equiv), Pd(OAc)2(10mol %),and Ag 2CO 3(2.2equiv) at 130°C. 15The reaction scope was next explored, revealing that it proceeds with moderate to excellent selectivity for the formation of monoarylated adducts and the extent of which varies on the substrates employed (Table3). For instance, reaction of 1a or its para derivative with benzene afforded the corresponding ortho phenylated products with a 3:1ratio (4/5) in high yields (entries1and 2). The ratio was increased up to 20:1when 3-substitued pyridine N -oxide was employed (entry3), indicating the importance of steric effects on the selectivity. Interestingly, phenylation of isoquinoline N -oxide with benzene provided 1-phenylisoquinoline 2-oxide as the major product (entry4).

Interestingly, N -oxides of quinoline and benzo[h ]quinolinewere arylated selectively at the ortho-position in good yields (entries5-6). It is noteworthy that since previous examples of the Pd-catalyzed direct coupling of benzo[h ]quinolineare shown to proceed selectively at the C(10)position, 16our present system offers a useful complementary route for the selective aryl introduction at the ortho position. Therefore, this may ser V e as a notable example of controlling site-selecti V ity by the employment of different directing groups within the same molecular skeletons . N -Oxides of pyrazine and quinoxaline were also readily cross coupled with benzene at the ortho position (entries7and 8).

It should be noted that homocoupling between employed arenes during the course of the direct arylation can be significantlyreduced down to 5%based on the equivalent of pyridine N -oxide used, when the reaction was carried out in the presence of pyridine or its derivatives, without deteriorating the reaction efficiencyand se-lectivity. 9

Preliminary survey on the scope of arenes revealed that the arylations indeed take place with a range of unactivated arenes. Cross-coupling of 1a with selected entries of 1,2-disubstituted arenes provides monoarylated products as major, and the reacting site on arenes was at the meta position relative to the 1,2-disubstituents of the arenes (entries9-11). Likewise, when 1,3-xylene was em-ployed, the reaction occurred at the meta position relative to the dimethyl substituents (entry12). 17

In summary, relying on the Pd-mediated C -H bond activation strategy, we have developed two highly promising oxidative protocols for the selective alkenylation and direct arylation of pyridine N -oxides using olefinsand unactivated arenes, respectively. Mechanistic studies toward the detailed understanding of the activation pathways and synthetic applications based on the present approaches are under way.

Acknowledgment. Dedicated to Professor Kwan Soo Kim on the occasion of his 60th birthday. This research was supported by the Korea Research Foundation Grant (KRF-2006-312-C00587).We also thank Dr. Junseung Lee for the crystal structure analysis.

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Supporting Information Available:Data and copies of 1H and 13C NMR spectra of new compounds and one CIF file.This material is available free of charge via the Internet at http://pubs.acs.org.

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(17)When than those substituted presented arenes in Table were employed, 3were observed no regioisomeric by 1products other

reaction mixture.

H NMR of the crude JA8026295