Synthesis of 2-substituted pyridines from pyridine N -oxides

The synthesis of substituted pyridines has drawn the attention of many chemists due to their importance as building blocks for biologically active compounds and materials. This mini-review focuses on recent developments relating to the synthesis of substituted pyridines from pyridine N -oxides, along with their interesting mechanism aspects. New developments including alkenylation, alkynylation, alkylation, arylation, amination and cyanation are discussed.


Introduction
Substituted pyridines are an important class of compounds in organic synthesis. 1The structural framework of substituted pyridines is often seen in natural products, compounds possessing important biological activities, and functional materials. 2Substituted pyridines are usually prepared starting from halo-or metallated pyridyl compounds.However, this method is commonly accompanied with problems and the formation of by-products.
Pyridine N-oxides 3 are very useful synthetic intermediates in the field of heterocyclic chemistry, since they are much more reactive towards both electrophilic and nucleophilic reagents than the heterocycles from which they are derived. 4Reactions of pyridine N-oxides is one of the most useful synthetic methods for the formation of various substituted pyridines and their derivatives.Over recent decades, pyridine N-oxides have drawn the attention of numerous research groups, and the number of new synthetic methodologies and modifications of traditional procedures has grown markedly, which has been reflected in the number of research publications in the literature.This mini-review focuses on recent developments relating to the synthesis of substituted pyridines from pyridine N-oxides along with their interesting mechanism aspects.Accordingly, we discuss only the most essential reactions here and summarize the recent contributions reported after 2002.

Transition Metal-catalyzed Alkenylation
Recently, Chang et al. reported highly promising oxidative protocol for the selective alkenylation of pyridine N-oxides 1 using olefins 2 relying on the palladium mediated C-H bond activation strategy (Scheme 1). 5 Various alkenylated pyridine N-oxides 3 were obtained in good to high yields.The resultant alkenylated pyridine N-oxides (e.g., 3a) were readily deoxygenated to give 2-alkenylpyridines 4, making the present alkenylation route a highly attractive alternative for the 2-functionalization of pyridine derivatives.In addition, Cui, Wu and co-workers revealed for the first time in Pd-catalyzed alkenylation of quinoline-and isoquinoline-N-oxides via C-H activation under external-oxidant-free conditions (Scheme 2).2) -H bonds of pyridine N-oxides 1 under mild conditions followed by regio-and stereoselective insertion of alkynes 8 to afford (E)-2-alkenylpyridine N-oxides 9 in modest to good yields (Scheme 3). 7The resulting adducts were readily deoxygenated to give various substituted pyridines 10.

Scheme 3
A plausible mechanism for the nickel-catalyzed alkenylation of pyridine N-oxides is shown in Scheme 4. Alkyne-coordinated nickel (0) species A underwent oxidative addition to the C2-H bond, giving the pyridyl(hydride)-nickel species B. Hydronickelation in a cis fashion then provided the alkenyl(pyridyl)nickel intermediate C. Coordination of the alkyne such that the steric repulsion between the bulkier R 3 and the pyridyl group in B was avoided would be responsible for the observed regioselectivities.Reductive elimination followed by coordination of an alkyne afforded 2-alkenylpyridine-N-oxide 9 and regenerated the nickel (0) species A. The N-oxide moiety played an important role in directing the metal catalyst to the proximal C2-H bond and/or making the C-H bond acidic enough to undergo the oxidative addition to nickel (0).

Scheme 4
Fagnou et al. reported palladium-catalyzed direct arylation reactions of pyridine N-oxides (azine and azole N-oxides 8,9,10 ) occur in excellent yield with complete selectivity for the 2-position with a wide range of aryl bromides 11.The resulting 2-arylpyridine N-oxides could be easily reduced to the free pyridine 12 via palladium-catalyzed hydrogenolysis (Scheme 5). 11

Scheme 5
A recent report by the same author revealed that lower yields were encountered with substrates bearing methyl substituents adjacent to the N-oxide moiety, they developed site selective arylation reactions of both sp 2 and benzylic sp 3 sites on pyridine N-oxide substrates and illustrate that reactivity could be performed both divergently and sequentially (Scheme 6). 12,13 rthermore, the N-oxide moiety could be used to introduce a wide range of other functional groups or could easily be deoxygenated under mild conditions.

Scheme 6
Direct arylation of pyridine N-oxides with aryl triflates can also be obtained.Fagnou et al. reported palladium-catalyzed direct arylation of pyridine N-oxides using aryl triflates to afford the corresponding 2-aryl pyridine N-oxides (Scheme 7). 14Differentially diarylated products could be obtained by carrying out tht arylation reactions in sequence as shown in Scheme 8. Pyridine N-oxide was arylated with p-tolyl trifluoromethanesulfonate in 89% yield.This product could then be resubmitted to arylation conditions with 4-methoxyphenyl trifluoromethanesulfonate under the more active conditions to generate the differentially diarylated compound 20 in 84% yield.Conditions A, which employed aryl triflates, resulted in not only higher yield than the previously reported conditions B (with aryl bromides) but also required less equivalents of intermediate 19.Therefore, it could be advantageous to employ aryl triflates when low yields were obtained with aryl bromides.

Amination
Yin et al. developed a general and efficient method to convert pyridine N-oxides to 2aminopyridines 23 in a one-pot process in high yields and high regioselectivity.The process used commercially available reagents t-BuNH2 and Ts2O and showed good functional group compatibility (Scheme 9). 15The use of t-BuNH2 was critical for shutting down side reactions such as dimerization and tosylation of the product as well as suppressing the reaction between the amine and the activating reagent Ts2O.TFA treatment of the crude reaction mixture effectively removed the t-Bu group.

Scheme 9
Londregan et al. reported a general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine N-oxides as a mild altermative to SNAr chemistry.The authors found that the phosphonium salt PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate) functioned as a general and mild N-oxide activator for the regioselective addition of amine nucleophiles.In this reaction, unhinderedaliphatic amines participated most effectively in the transformation, but aminations using heterocycles, such as imidazoles and pyrazoles, unexpectedly proceeded (Scheme 10). 16The mechanism of the reaction is shown in Scheme 11.The reaction proceeded via the activated pyridine complex 24.Subsequent basic rearomatization 25 afforded the desired 2-aminopyridine 23 and phosphoryltripyrrolidine 26, the only significant organic byproduct of the reaction.Recently, the same group also found that reactions could be expanded into broader classes of nucleophiles (such as phenol, sulfonamide, malonate, pyridone, thiol) after minimal reaction optimization of original amination procedure.The presented reactions represented a very large and varied set of putative nucleophiles and N-oxides. 17A one-pot method for the generation of imidoyl chlorides and their subsequent in situ reaction with pyridine N-oxides was developed by Manley and Bilodeau (Scheme 12). 18The imidoyl chlorides were formed from the reaction of secondary amides with a stoichiometric amount of oxalyl chloride and 2,6-lutidine in CH2Cl2 at 0 o C. Upon warming of the reaction mixture to room temperature in the presence of pyridine N-oxides, a rapid conversion to 2aminopyridine amides 28 was observed in moderate to excellent isolated yields.

Scheme 12
Keith reported a convenient one-step procedure for the conversion of pyridine N-oxides to 2imidazolopyridines 30 in fair to excellent yield through the action of sulfuryl diimadazole at elevated temperatures. 19A possible mechanism for the activation and substitution of pyridine Noxides with potential side reactions is shown in Scheme 13.Recently, same researcher also developed a method for the deoxygenative coupling of pyridine N-oxides with azoles through the use of preformed tosylazole reagents.The methodology allowed for the introduction of 1,2,4-and 1,2,3-triazoles, imidazole, and electrondeficient pyrazoles on pyridine (Scheme 14). 20.

Cyanation
Recently, Yamamoto et al. reported a convenient method for the direct synthesis of 2-cyanoisonicotinamide 35 from isonicotinic acid N-oxide using zinc cyanide as a cyanation reagent (Scheme 15). 21The reaction mechanism is shown in Scheme 16.

Scheme 19
Olsson and Almqvist et al. also developed a mild method for the selective 2-substitution pyridine N-oxides 44 via a directed ortho-metallation.Addition of i-PrMgCl to pyridine Noxides in THF at -78 o C generated selectively an ortho-metallated species, which could be trapped with various electrophiles, ranging from aldehydes, ketones and halogens, to generate 2substituted pyridine N-oxides (Scheme 20). 24Additionally, Duan et al. also reported similar results.2-Bromopyridine N-oxides were readily magnesiated with i-PrMgCl .LiCl via brominemagnesium exchange.The bromine adjacent to pyridine N-oxide (at 2-or 6-position) could be selectively magnesiated in the presence of halogens substituted at other positions (Scheme 21).

Scheme 20 Scheme 21
Recently, Itami and Li et al. reported transition-metal-free systems for the cross-coupling reactions of nitrogen heteroaromatics and alkanes.Under the influence of tBuOOtBu, pyridine N-oxide derivatives reacted with alkanes to furnish the corresponding cross-coupling products (alkylated nitrogen heterocycles) in good yields.The present oxidative cross-coupling reactions at two different C-H bonds not only contributed to the realization of "greener" synthesis, but also unlocks opportunities for markedly different strategies in chemical synthesis (Scheme 22). 26Scheme 22

Transition-metal Free Alkynylation
Chupakhin et al. reported a method for the direct introduction of acetylenes into heterocyclic systems using SN H methodology.It provided a versatile tool for the synthesis of a series of ethynyl azines.The method requires no expensive reagents, and can be used as a complementary method to Sonogashira cross-coupling reactions (Scheme 23).

Palladium-catalyzed Direct (Hetero)arylation
You, Hu, and co-workers recently reported for the first time in Pd(II)-catalyzed, copper(I)promoted oxidative cross-coupling between pyridine N-oxides and electron-rich heteroarenes such as furans and thiophenes, where Cu(OAc)2 .H2O was used as an oxidant (Scheme 24). 28lausible catalytic cycle of oxidative C-H/C-H cross-coupling of heteroarenes with pyridine Noxides is shown in Scheme 25.In the first metalation step, the abstraction of hydrogen from thiophene took place in the reaction system.Thus, thiophene would undertake a regioselective electrophilic C-H substitution (SEAr) of Pd(OAc)2 to generate α-thienylpalladium(II) intermediate 51.Then it reacted with N-oxide to form the key heterocoupling intermediate 52, which might be rate-determining in the entire reaction.

Conclusions
In summary, we have described some recent advances in the synthesis of various types of 2substituted pyridines from pyridine N-oxides.The significance of development of synthetic methods is that it provides a useful alternative to classic approach, which has usually prepared starting from halo-or metallated pyridyl compounds.However, pyridine N-oxide is now being more popular because of its efficiency, and many new methods will probably be developed for the synthesis of 2-substituted pyridines in the near future.