15.1.4 Pyridines (Update 2016)

D. Spitzner

General Introduction

The following sections contain examples of the synthesis of pyridines and pyridine derivatives, updating the earlier Science of Synthesis chapter (Section 15.1).

15.1.4.1 Pyridines

Pyridines are substructures in many natural products, and numerous methods are available for their synthesis. Microreaction technology is generally defined as the continuous processing of reactions through flow systems that have a diameter of less than 1000 μm; such systems have been applied in the synthesis of pyridines.[1] General aspects of the synthesis and the properties of pyridines are available in reviews and monographs.[2–23] Computational thermochemistry (the W3.2lite protocol) has been successfully applied to pyridine, as well as other aromatic and aliphatic hydrocarbons.[24]

Important pyridine derivatives include 4-(dimethylamino)pyridine (DMAP), developed by Höfle and Steglich, which is still a very effective catalyst and is widely applied in organic synthesis.[25] This catalyst is very sensitive to its electronic environment. Bipyridine molecules bearing donor substituents in their π backbone are examples of “push–pull” molecules, possessing emissive properties in the visible region at room temperature.[26] Pyridinecarbonitriles have been found to be promising fluorescent dyes that exhibit high quantum yields, low pH dependence, and high sensitivity to solvent polarity.[27] Functionalized 2,2′:6′,2″-terpyridines are used in dye-sensitized solar cells.[28,29] Pyridine is a substructure of the high-potency sweetener NC-00 637. Zinc complexes of disubstituted bipyridine with (trimethylammonio)methyl groups have been used as artificial nucleases.[30]

The pyridine moiety is part of the structure of various biologically active compounds, such as drugs or pesticides. Examples include esomeprazole (Nexium; administered in salt form), afidopyropen,[31] and flucetosulfuron (FLUXO), which is a sulfonylurea herbicide used particularly in Asia.[32] Neonicotinoids, such as imidacloprid, are very effective insecticides, but are suspected to harm adult worker honey bees (Apis mellifera L) (▶ Scheme 1).[33]

A range of dearomatizing π-bases having the general form {M(Tp)(L)(π-acid)} [M = Re, Mo, W; Tp = hydridotris (pyrazolyl) borate; L = variable ligand; π-acid = CO, NO+] have been developed[34,35] that facilitate the Diels–Alder reaction of pyridine with dienophiles to form intermediates attractive for the synthesis of various alkaloids (▶ Scheme 2).[36–38] 2-(Dimethylamino) pyridine (2-DMAP) is dearomatized by {W(Tp)(PMe3)(NO)}.[39,40]

Pyridines undergo addition of pinacolborane at 50 °C in the presence of a rhodium catalyst, giving N-boryl-1,2-dihydropyridines 1 in high yield (▶ Scheme 3).[41] Pyridines undergo regioselective 1,4-hydroboration by organoborane catalyzed reaction.[42] 1,4-Hydrosilylation products are obtained from pyridines in the presence of ruthenium catalysts.[43] Thus, the complexes [RuCp{P(iPr)3}(NCMe)2]+ and [RuCp{P(iPr)3}(NCMe)2][B (C6F5)4] catalyze the regioselective hydrosilylation of pyridines to 1,4-dihydropyridines.[43,44]

The palladium-catalyzed regioselective silaboration of pyridines leading to the synthesis of silylated dihydropyridines (▶ Scheme 3) offers an alternative method to the conversion of pyridine into dihydropyridines via pyridinium compounds.[45] Functionalized 1,2-dihydropyridines are also obtained by a copper-catalyzed Perkin–acyl-Mannich reaction of acetic anhydride with pyridine.[46] Nucleophiles add regio- and stereoselectively to N-activated pyridines to give other pyridines and di- or tetrahydropyridines.[47–49]

The pyridine ring (even pyridine itself) can be opened, for example by photolysis in water. This reaction gives the very unstable 5-aminopenta-2,4-dienal, which cyclizes back to pyridine.[50]

Reactions of the overcrowded silylene 2 with pyridines lead to novel 2H-1,2-azasilepine derivatives (▶ Scheme 4).[51]

The abstraction of two substituents from pyridine rings gives pyridynes, which are reactive intermediates.[52] Pyridynes are accessed from pyridylsilyl trifluoromethanesulfonate precursors using mild fluoride-based reaction conditions.[52–55] 3,4-Pyridyne 3, in contrast to 2,3-pyridyne, reacts with nucleophiles with poor regioselectivity; in addition to product 4, 10% of the corresponding C3 regioisomer is also obtained (▶ Scheme 5).[54]

3,4-Pyridynes and 2,3-pyridynes react with various organic azides under mild conditions to afford the corresponding [1,2,3]triazolo[4,5-c]pyridines and [1,2,3]triazolo[4,5-b]pyridines, respectively. In the case of the reaction of 3,4-pyridyne, it was also found that a substituent on the pyridine ring affects the regioselectivity of the cycloaddition.[56]

Reduction and hydrogenation are possible with complex hydrides, under catalytic conditions, and electrochemically. Piperidines are mainly obtained with hydrogen in the presence of heterogeneous or homogeneous catalysts. The hydrogenation of various aromatic compounds, including pyridines, may be performed in water. This seems to be a mild and facile method.[57]

Pyridines give highly deuterated substituted piperidines with deuterated ammonium formate as deuterium source; an example is shown in ▶ Scheme 6.[58] A metal-free direct hydrogenation of pyridines using homogeneous borane catalysts generated from alkenes and bis (pentafluorophenyl)borane via in situ hydroboration affords a broad range of piperidines in high yields with excellent cis stereoselectivities.[59]

Methodology for the synthesis of natural products containing a pyridine substructure has been reviewed;[20,60] an overview of modern methods for nitrogen-heterocycle formation via C—H bond functionalization is also available.[61]

In the synthesis of the alkaloid complanadine A (▶ Scheme 7), the Hartwig–Miyaura iridium(I)-catalyzed site-selective borylation[62] and a late-stage Suzuki cross coupling were applied to form the C2–C3′ unit.[63] A Suzuki cross coupling using Buchwald's Cy-JohnPhos and XPhos ligands has been applied as the key step in the synthesis of micrococcinate and saramycetate esters.[64]

Piericidins have been obtained by total synthesis involving classical Julia–Lythgoe alkenation.[65] The synthesis of arctic sponge alkaloid viscosaline (▶ Scheme 7) has been achieved using the Zincke reaction as the penultimate step.[66] A key synthetic intermediate, theonelladine C, itself a marine sponge natural product, is synthesized efficiently using a four-step sequence. Nicotine,[67] pyrinadine A,[68] and jasminine[69] are interesting simple pyridine alkaloids that have been synthesized and modified. The chemistry of the more complex pyridine natural product streptonigrin has been reviewed.[70] New anti-inflammatory pyridine compounds have been isolated from Monascus pilosus fermented rice.[71] The pyridine ring is part of the rather complex natural product thiocillin I (▶ Scheme 7) and micrococcin P1, GE2270A, and amythiamicin C and D thiopeptide antibiotics.[72–77] Topsendines A–F are new 3-alkylpyridine alkaloids from a Hainan sponge Topsentia sp.[78]