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Synthesis 2009(8): 1400-1402  
DOI: 10.1055/s-0028-1088009
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© Georg Thieme Verlag Stuttgart ˙ New York

Rhodium-Catalyzed Gram-Scale Synthesis of Highly Substituted Pyridine Derivatives

Kanniyappan Parthasarathy, Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
Fax: +886(3)5724698; e-Mail: chcheng@mx.nthu.edu.tw;

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Publication History

Received 15 November 2008
Publication Date:
06 March 2009 (online)

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Abstract

Rhodium-catalyzed chelation-assisted activation of the β-C-H bond of α,β-unsaturated ketoximes and subsequent reaction with alkynes affords highly substituted pyridine derivatives. This new method provides an opportunity for the one-pot synthesis of pyridines with all five positions (C2-C6) substituted.

Key words

pyridine - ketoxime - rhodium - C-H activation

Introduction

Scheme 1 Synthesis of 2,3,4-trimethyl-5,6-diphenylpyridine (3a)

Substituted pyridines are an important class of heterocyclic compounds. [¹] The pyridine core is one of the most prevalent heterocycles found in pharmaceuticals, agrochemicals, and natural products. [²] The majority of synthetic routes to pyridine rings are based on condensation reactions of amines with carbonyl compounds, [³] Diels-Alder­ reactions with 1-azadienes, [4] and metal-catalyzed cycloaddition reactions. [5] Herein, we wish to describe a very convenient and gram-scale synthesis of highly substituted pyridines from α,β-unsaturated ketoximes and alkynes via rhodium-catalyzed activation of the β-C-H bond of the α,β-unsaturated ketoxime. Preliminary results of this catalytic reaction have appeared. [6] The starting materials, the α,β-unsaturated ketoximes, are easily prepared by condensation of α,β-unsaturated ketones and hydroxyl­amine hydrochloride in the presence of sodium acetate using­ methanol as the solvent. [7]

Treatment of α,β-unsaturated ketoxime 1a, with methyl substituents at the α- and β-carbons, with diphenylacetylene (2a) in the presence of 3 mol% of chlorotris(triphenylphosphine)rhodium in toluene at 130 ˚C for five hours gave the highly substituted pyridine derivative 3a in 84% isolated yield (Scheme  [¹] , Table  [¹] ). The formation of product 3a can be viewed as β-alkenylation of oxime 1a to provide a 1-azatriene intermediate, followed by 6π-cyclization and dehydration (vide infra).

Table 1 Results of the Reaction of α,β-Unsaturated Ketoximes with Alkynes

Entry Oxime
 Alkyne
 Product Yielda
R¹ R² R³ R4 R5 (%)
1 1a Me Me Me 2a Ph Ph 3a 84
2 1b H H Me 2a Ph Ph 3b 61
3 1c Ph H Me 2b Et Et 3c 73
4 1d (CH2)3
Me 2c Ph TMS 3d b 77
5 1a Me Me Me 2d Me Me 3e 69
a Isolated yield. b R5 = H.

The scope of this method was extended with various α,β-unsaturated ketoximes 1b-d and symmetrical and unsymmetrical alkynes (Table  [¹] ). Thus, methyl vinyl ketoxime 1b reacted with 2a to give the corresponding substituted pyridine 3b in 61% yield. It is interesting to note that oxime 1c with a phenyl group at the β-carbon reacted nicely with hex-3-yne (2b) to give the expected pyridine derivative 3c in 73% yield, but failed to react with diphenylacetylene (2a). The steric repulsion between the phenyl groups in 1c and 2a likely accounts for the failure of this reaction. To understand the regioselectivity of the present reaction, the reaction of unsymmetrical alkyne, 1-phenyl-2-(trimethylsilyl)acetylene (2c), with 1d in a high regioselective manner provided desilylated pyridine derivative 3d in 77% yield in which the phenyl group was attached to C4 of 3d. The regiochemistry of 3d was confirmed by NOE experiments. Similarly 1a reacted with but-2-yne (2d) to give the corresponding 2,3,4,5,6-pentamethylpyridine (3e) in 69% yield. In this reaction, three equivalents of alkyne 2d were required to achieve a good yield of 3e.

A possible mechanism for the rhodium-catalyzed cyclization of α,β-unsaturated ketoximes with alkynes is shown in Scheme  [²] . [6] [8] Coordination of the nitrogen atom in ketoxime 1 to the rhodium(I) center followed by C-H bond activation gives a five-membered hydridoazametalacycle 4. Insertion of alkyne 2 into the Rh-H bond of 4 affords an alkenyl-Rh intermediate 5. Reductive elimination of 5 gives 1-azatriene 6. A 6π-cyclization of 6 followed by dehydration provides the final pyridine product 3.

Scheme 2  Proposed mechanism

In conclusion, we have developed a rhodium-catalyzed gram-scale synthesis of highly substituted pyridine derivatives. This method is technically simple and can readily provide pyridines substituted in all five positions (C2-C6) in one pot.

All reactions were conducted under an N2 atmosphere on a dual-manifold Schlenk line unless otherwise mentioned and in oven-dried glassware. All solvents were dried according to known methods and distilled prior to use. [9] RhCl(PPh3)3 was prepared by a previously published method. [¹0] For all products, physical and spectroscopic data are given in ref. 6.

2,3,4-Trimethyl-5,6-diphenylpyridine (3a); Typical Procedure for Gram-Scale Synthesis

A screw cap sealed tube (100 mL) initially fitted with a septum containing 3-methylpent-3-en-2-one oxime (1a, 2.00 g, 0.0176 mmol), diphenylacetylene (2a, 3.78 g 0.021 mmol), and RhCl(PPh3)3 (3.0 mol%) was evacuated and purged with N2 (3 ×). Freshly distilled toluene (20 mL) was added to the system and the mixture was stirred at 130 ˚C for 5 h. Initially the mixture was pale yellow in color, after 10 to 15 min it gradually became red and finally it became dark brown after 5 h. When the reaction was complete, the mixture was cooled and diluted with CH2Cl2 (100 mL). The mixture was filtered through a Celite pad and the Celite pad was washed with additional CH2Cl2 (50 mL). The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane-EtOAc) to give pure substituted pyridine derivative 3a (84% isolated yield).

Similar procedures were employed for the preparation of compounds 3b-e. For the reactions with unsymmetrical and aliphatic alkynes, 2 equivalents of alkynes relative to 1 and a reaction time of 12 h were employed.

Mp 59-61 ˚C.

IR (KBr): 3054, 2923, 1453, 1550 cm-¹ (C=N).

¹H NMR (400 MHz, CDCl3): δ = 7.71-7.23 (m, 5 H), 7.11-7.09 (m, 3 H), 7.02-7.00 (m, 2 H), 2.62 (s, 3 H), 2.29 (s, 3 H), 2.07 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 159.4, 154.0, 144.2, 141.2, 139.3, 133.8, 130.6, 129.7, 128.8, 127.9, 127.4, 126.7, 126.6, 23.5, 17.5, 15.4.

HRMS (EI): m/z [M]+ calcd for C20H19N: 273.1517; found: 273.1521.

2,3,4,5,6-Pentamethylpyridine (3e)

Mp 49-51 ˚C.

IR (KBr): 2992, 2926, 2730, 1587 cm-¹ (C=N).

¹H NMR (400 MHz, CDCl3): δ = 2.42 (s, 6 H), 2.15 (s, 6 H), 2.14 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 152.2, 143.6, 127.0, 23.2, 15.7, 15.1.

HRMS (EI): m/z [M]+ calcd for C10H15N: 149.1204; found: 149.1205.

Acknowledgment

We thank the National Science Council of the Republic of China (NSC-96-2113M-007-020-MY3) for support of this research.

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Scheme 1 Synthesis of 2,3,4-trimethyl-5,6-diphenylpyridine (3a)

Scheme 2  Proposed mechanism