Synthesis of substituted pyridines—III - ResearchGate
Sharpless, Chemoselective Synthesis of Polysubstituted Pyridines from Heteroaryl Fluorosulfates.
Novel synthesis of 3-substituted pyridines from pyridine
The first step of this three-component coupling strategy to de novo pyridines based on selective 1,2-addition of a dithiane anion to an α,β-unsaturated ketone or aldehyde typically proceeds with very high levels of efficiency. As depicted in , a range of substituted allylic alcohols can be prepared by this process including those that contain secondary and tertiary alcohols as well as mono-, di- and tri-substituted alkenes (6–23).
AB - Methods for a facile high-yielding synthesis of substituted pyrazolo[3,4-c]pyridines from 2-bromo-5-fluoropyridine are described, along with a brief mechanistic discussion for the key cyclization step. The methods utilize inexpensive commercially available starting materials and unlike previous methods, are more suitable for SAR work and scale-up.
Synthesis of trifluoromethyl-substituted pyrazolo[4,3- …
A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed TMS-imines (generated in situ by the low temperature reaction of LiHMDS with an aldehyde) and Ag(I)-, or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.
Aromatic nitrogen heterocycles play prominent roles in natural products and pharmaceutical agents. Of these, substituted pyridines are particularly abundant. As a result, pyridine synthesis has attracted the attention of members of the scientific community for more than 140 years. While many chemical methods exist for the preparation of these heteroaromatics, the search for new strategies that offer concise and regiospecific access remain a topic of considerable interest.
Synthesis of 2-substituted pyridines from pyridine N …
With our sights set on the development of a highly convergent pyridine synthesis that proceeds from readily available starting materials, we have focused on realization of the retro-synthetic strategy depicted in . Here, four central bonds of the pyridine are targeted for synthesis via stepwise union of an aldehyde 2, an α,β-unsaturated carbonyl system 3, and a dithiane 4 through a process that delivers pyridine products as single regioisomers.
This proposed strategy marks a substantial departure from traditional approaches based on carbonyl condensation chemistry (i.e. Hantzch-like dihydropyridine synthesis) and offers great flexibility in the nature and substitution of the pyridine products that can be accessed. Aside from the present study, a great many modern advances have been described that provide access to substituted pyridines by synthesis strategies that embrace a variety of diverse modes of chemical reactivity and key bond forming reactions that are distinct from those under pursuit. As illustrated in , these include Ru-catalyzed cycloisomerization, Cu-catalyzed cross-coupling of vinylboronic acids and oxime O-carboxylates, Rh-catalyzed C–H activation/alkyne insertion, Rh-carbenoid-catalyzed ring expansion of isoxazoles, electrophilic activation of vinyl-/aryl-amides and subsequent coupling with π-nucleophiles, cycloaddition, and ring closing metathesis (not depicted).
Synthesis and biological activity of 3-substituted …
Synthesis and Reactions of 2- and 4-Substituted Furo[3…
Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines – sequential versus multicomponent reaction approach
of 2- and 4-Substituted Furo[3,2- ]pyridines ..
Synthesis of meta-substituted [18 F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides
The synthesis of new 3,4,5-trialkylated pyridines ; part 2
Synthesis and reactions of 2-and 4-substituted furo[3,2 …
Pyridine synthesis - Organic Chemistry Portal
N2 - Methods for a facile high-yielding synthesis of substituted pyrazolo[3,4-c]pyridines from 2-bromo-5-fluoropyridine are described, along with a brief mechanistic discussion for the key cyclization step. The methods utilize inexpensive commercially available starting materials and unlike previous methods, are more suitable for SAR work and scale-up.
Pyrrole synthesis - Organic chemistry
While built on our recently described three-component coupling reaction for the synthesis of primary homoallylic amines from the union of aldehydes with LiHMDS and an allylic alcohol, the current pursuit was aimed at accomplishing a significantly more demanding process. The increased challenges associated with this pursuit span considerations regarding both reactivity and stereoselectivity. First, chemical compatibility of the dithiane group of 5 with the reaction conditions for Timediated coupling was thought to define a potential barrier to success. It is well established that low-valent Ti-reagents (specifically, Cp2Ti-) are capable of converting dithianes to the corresponding metal-carbene, and elegant examples of this process have been employed in synthesis campaigns. Second, our established Ti-mediated allylic alcohol–imine coupling process is not uniformly (Z)-selective. If (Z)-selectivity in the union of 2 and 5 is necessary to enable subsequent ring closure/oxidation to the pyridine, then only a small subset of substituted allylic alcohols would be of utility in this process (R3 ≠ H; R2 = H). As such, the general strategy depicted in had the potential of being rather limited in its ability to access a range of substituted pyridines. That said, if conditions for cyclization could be found to enable rapid and reversible alkene isomerization prior to ring closure, the strategy depicted in would be of extremely broad utility as a means to access a great variety of differentially substituted pyridines.
Thieme E-Books & E-Journals - Synthesis / Issue
With sights now set on the metallacycle-mediated coupling step of the planned pyridine synthesis, we examined the reactivity of allylic alcohol 6 in Ti-mediated reductive cross-coupling with aldehyde 24 (). Here, we were delighted to find that convergent coupling proceeded effectively, despite the presence of the dithiane, and the primary homoallylic amine product was advanced to the 2,4-disubstituted pyridine 25 in 53% yield (over the two-step sequence) as a single substitutional isomer. While we did not isolate the proposed homoallylic amine intermediate in this sequence, previous experiences with Ti-mediated reductive cross-coupling reactions of related allylic alcohol (i.e. those containing 1,1-disubstituted alkenes) led to the expectation that this coupling reaction proceeds with very high levels of (Z)-selectivity ().
Benzyne Click Chemistry: Synthesis of Benzotriazoles …
With a firm foundation of results supporting the great flexibility of this pyridine synthesis for the preparation of 2-Ph-substituted pyridines, effort was focused on exploring the suitability of this process for preparing pyridine analogs that contain varying substituents about the heterocycle core. As illustrated in , eqs 1–8, a range of substituted mono- and bicyclic pyridines are easily accessible from the Ti-mediated reductive cross-coupling/cyclization sequence of aromatic and aliphatic aldehydes with suitably functionalized allylic alcohols. Overall, the substituted pyridine products from this process contain additional heteroaromatics [i.e. thiophenes (39, 44 and 47) and furans (41)], electron rich and electron poor aromatics [including arylfluorides (49) and arylchlorides(51)], as well as aliphatic groups (43) and fused ring systems (46, 47, and 49).
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