Preparation of substituted alkoxypyridines via directed metalation and metal-halogen exchange

Several halo-substituted alkoxypyridines were prepared and subjected to directed metalation and metal-halogen exchange reactions. The studies resulted in useful methods for synthesis of numerous substituted pyridines via regioselective lithiation, magnesation and halogen dance reactions


Introduction
Various alkoxypyridines are found in pharmaceutical agents, [1][2][3] electronic materials, 4 liquid crystals, 5 organometallic complexes, [6][7][8] and oligomers. 9They also have been used as synthetic building blocks for natural products and medicinal agents. 10Over the years, for use in our alkaloid total synthesis projects, 11 several derivatives of alkoxypyridines have been prepared using directed metalation and metal-halogen exchange reactions.Reported herein are many examples that resulted from these efforts.

Results and Discussion
Much of our work in this area started with 4-methoxypyridine which is commercially available or can be easily made from 4-chloropyridine hydrochloride by nucleophilic substitution with sodium methoxide.Directed lithiation at the C-3 position can be carried out using mesityllithium (MesLi) 12,13 or PhLi 14 in THF to give good yields of products 1 on addition of electrophiles (Scheme 1).Scheme 1. C-3 lithiation and substitution of 4-methoxypyridine.
With compound 9 in hand, our next goal was the synthesis of alcohol 10.We anticipated it could be accomplished from the methoxy-directed lithiation of 9, followed by trapping the lithiated pyridine with DMF, and then sodium borohydride reduction of the resulting aldehyde.Initial treatment of 9 with LTMP for 60 minutes prior to trapping with DMF generated the regioisomer 11 via a halogen dance mechanism.Reduction of 11 with sodium borohydride gave the corresponding alcohol 12. Fortunately, metalation of 9 with LDA for 5 minutes prior to addition of DMF provided the desired alcohol 10 on in situ reduction (Scheme 6).A mechanism study on the lithiation of 2-methoxypyridine with LDA vs LTMP has been reported by Fort and coworkers. 20The conversion of 10 to the [1,3]-dioxinopyridine 13 was carried out via a one-pot reaction 16 in good yield (Scheme 6).Scheme 6. Synthesis of dibromopyridines 10-13 from 2,5-dibromo-4-methoxypyridine (9).
The regioselective lithiation and magnesation of 13 was examined.The [1,3]-dioxinopyridine 13 was treated with 1.0 equivalent of n-butyllithium at -78 °C for 10 min, and the resulting lithiopyridine was quenched with water.The 1 H NMR spectrum of the product was consistent with C-5 lithiation to give compound 5.This regioselective lithiation is the same as that observed for 2,5-dibromopyridine; 21 however, when 13 was treated with 1.2 equivalents of isopropylmagnesium chloride, the 1 H NMR spectra of the resulting product obtained from quenching with water indicated that 14 was the product.This regioselective C-2 magnesation is in sharp contrast with the observed C-5 magnesation of 2,5-dibromopyridine. 22 Lithiumhalogen exchange at C-5 of 13 with n-butyllithium followed by addition of 2-chloroquinoline-3-carbaldehyde provided alcohol 15.Conversion of 15 to the bromide 16 was carried out using triphenylphosphine, 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tetra-n-pentylammonium bromide in dichloromethane. 23inc modified cyanoborohydride reduction 24 of compound 16 using zinc chloride and sodium cyanoborohydride in refluxing ether/THF provided compound 17 (Scheme 7).The assigned structure of compound 17 was confirmed by X-ray crystallography.

Scheme 7. Regioselective metalation of [1,3]-dioxinopyridine 13.
The metal-halogen exchange reactions of 2,5-dibromo-4-methoxypyridine (9) were also investigated.Treatment of 9 with n-BuLi followed by quenching of the lithiopyridine with water afforded 2. It was observed that when the reaction between 9 and n-BuLi was allowed to proceed for 30 minutes prior trapping the lithiopyridine with DMF or ethyl formate, the aldehyde 3 was the observed product.In contrast, when a mixture consisting of 9 and ethyl formate was treated with n-BuLi, aldehyde 18 was generated.In addition, trapping the lithiopyridine with DMF within 5 minutes of reaction also resulted in 18.The formation of 3 from 9 must occur via a C-5 to C-3 lithium migration.A similar observation has been reported for other dibromopyridines. 25When 9 was treated with isopropylmagnesium chloride at room temperature, addition of 2-chloroquinoline-3-carbaldehyde gave a good yield of alcohol 19 (Scheme 8).Scheme 8. Regioselective metalation/substitution of 2,5-dibromo-4-methoxypyridine (9).
Since iodopyridines can be precursors to alkoxypyridines, the metalation/substitution of 2,5-dibromo-4iodopyridine (8a) with LDA was investigated.Treatment of 8a with LDA (or LTMP) and DMF (or EtOCHO), followed by in situ reduction generated either alcohol 21 or 22 depending on how long lithiation was allowed to proceed prior to trapping with the formylating agent.If LDA is used and ethyl formate is added after only 5 minutes, the C-6 position is formylated leading to alcohol 21 after NaBH4 reduction.Using LTMP as base and increasing the lithiation time to 30 minutes provided the alcohol 22 as the product in good yield (Scheme 9).Scheme 9. Lithiation and halogen dance reactions of trihalopyridine 8a.
Trihalopyridine 22 was protected as the MOM ether 23 and subjected to n-BuLi followed by addition of trimethylborate and oxidative workup to give pyridinol 24 in good yield.The assigned structure of 24 was confirmed by NMR and X-ray crystallography.As depicted in Scheme 9, the position of the iodine and bromine substituents at C-2 and C-3 of compounds 22 and 23 could not be determined conclusively.Either isomer of 23 could be a precursor to product 24.Isomer 23a could undergo lithium-iodine exchange at C-2 followed by a halogen-dance to give the C-3 pyridyllithium that leads to 24. 26 Direct lithium-iodine exchange at C-3 of 23b would give the same required intermediate.On treatment with BF3 etherate, 24 was converted to the dioxinopyridine 25.Regioselective lithium-halogen exchange occurs at C-2 of 25 with n-butyllithium in THF at low temperature to give 26 on quenching with water (Scheme 9).

Conclusions
The directed metalation and metal-halogen exchange reactions of various halo-substituted alkoxypyridines were found to be very regioselective.These and the halogen-dance transformations observed should be useful for the preparation of other numerous pyridine derivatives.During the course of these studies, several novel dioxinopyridines were prepared.These compounds have the potential to act as precursors to highly functionalized pyridines, pyridones, and pyridinols.

Experimental Section
General.All reactions were performed in oven or flame-dried glassware under argon or nitrogen atmosphere and stirred magnetically.Tetrahydrofuran (THF), ether, and toluene were distilled from sodium/benzophenone ketyl prior to use.Triethylamine, diisopropylamine, diisopropylethylamine, N,N'dimethylethanolamine, 2,2,6,6-tetramethylpiperidine, ethyl formate, dimethylformamide, and benzene were distilled from calcium hydride and stored under argon over 4A molecular sieves.Other reagents and solvents from commercial sources were stored under argon and used directly.Melting points were obtained from a Thomas-Hoover capillary melting point apparatus and are uncorrected.Radial preparative layer chromatography (radial PLC) was performed using glass plates coated with 1, 2, or 4 mm layers of Kieselgel 60 PF254 containing gypsum.High-resolution mass spectral analysis (HRMS) was performed at North Carolina State University.X-ray spectral analysis was performed at North Carolina State University using Apex2 diffractometer.Elemental analyses were performed by Atlantic Microlab Inc. NMR spectra were obtained using a Varian Gemini GN-300 (300 MHz), Varian Mercury 300 (300 MHz), or Varian Mercury 400 (400 MHz) spectrometer.Chemical shifts are in δ units (ppm) with TMS (0.00 ppm) used as an internal standard for 1 H NMR and CDCl3 absorption (77.23 ppm), CD3OD absorption (49.15 ppm), or DMSOd6 absorption (39.51 ppm) for 13 C NMR spectra.IR spectra were recorded on a Perkin-Elmer 1430 spectrometer.