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Synthesis of 2,3-Dihydropyridinium and Pyridinium Derivatives

An Improved Chichibabin Pyridine Synthesis1

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Chichibabin pyridine synthesis - Wikipedia

For example, during investigations on the reactivity of indolizinones, we required efficient access to an alkylated variant of pyridyl alcohol 1 (). After extensively investigating various methods for the introduction of a butyl group at C(6) of 1, it was determined that only the direct, Chichibabin-type reaction with n-BuLi furnished the desired product. We postulated that pyridyl alcohols could offer a general solution to the traditional challenges associated with an alkylative Chichibabin-type process. First, by deprotonation of the alcohol group (e.g., in 2, ) with an appropriate base, an alkoxide intermediate would be formed (see 3), which would be slow to undergo lateral deprotonation (e.g., upon treatment with an alkyl lithium reagent). Second, a potential interaction between the alkoxide counter-cation (M) and the pyridine nitrogen of 3 would enhance the electrophilicity at C(6) and also increase the basicity of the alkoxide lone pairs. This potential increase in basicity of the alkoxide was expected to enhance interactions with organometals (see 3a), which would in turn increase the nucleophilicity of the organometallic toward the pyridine nucleus and also direct its delivery to the proximal C(6) position of 3 (in preference to C(4)). Finally, loss of LiH and protonation would provide the desired C(6)-alkylated pyridyl alcohol (5).

derivatives by the reaction of pyridine with ..

Direct C(6) alkylation of pyridyl alcohols can be achieved following an initial deprotonation of the hydroxy group. This transformation, which is believed to occur by a Chichibabin-type alkylation, avoids lateral deprotonation prior to pyridine ring alkylation and gives increased regioselectivity for C(6) over C(4) alkylation.

Chichibabin pyridine synthesis - Revolvy

Mikroyannidis, & mechanism chichibabin pyridine synthesis reaction m

To test this hypothesis, we initiated our studies on the direct alkylation of pyridyl alcohols with 1 (see ), which was prepared from commercially available 2,3-cycloheptenopyridine using a Boekelheide oxidation sequence. Pyridyl alcohol 1 was treated sequentially with a range of bases followed by n-BuLi as the alkyl nucleophile. Thus, using n-BuLi as the base (23 °C, 0.5 h), followed by an additional 1.1 equivalents of n-BuLi as the nucleophile, and stirring at 23 °C for 44 h resulted in 65% conversion to 6 after quenching (with MeOH) and a standard workup (entry 1). Increasing the temperature to 60 °C (entry 2) led to 6 in essentially the same conversion but in a shorter reaction time period (24 h). Upon heating the reaction mixture to 110 °C (entry 3), conversion to 6 (71%) was also observed, along with some byproducts. Interestingly, employing NaH (entry 4) as the base resulted in only 10% conversion, whereas the use of EtMgBr (entry 5) or n-BuMgCl (entry 6) as base did not lead to productive reaction and resulted in the recovery of the starting material.

The optimal reaction conditions (outlined in , entry 3) were applied to a range of substrates as illustrated in (see 7–14; only products are shown). Notably, in the absence of the hydroxy group, polymerization or decomposition was observed for the majority of substrates (e.g., 7a or 11a), suggesting an important role for the hydroxy group. Acyclic pyridyl alcohols gave modest to good isolated yields of the alkylated products (see 7b; 8–12). For cyclic pyridyl alcohols, only the 7- and 8-membered ring substrates gave satisfactory yields of the alkylated products (compare 13 to 14–17). Primary and secondary alkyl lithium reagents were competent nucleophiles (e.g., see 14 and 15, respectively), whereas tertiary alkyl lithiums (see 16) and aryl lithium nucleophiles (see 18) led to reduced yields of the adducts (in the latter case, presumably due to competing lithiation of the newly introduced benzene ring).

Biomimetic Chichibabin Pyridine Synthesis of the COPD Biomarkers ..

Chichibabin Pyridine Synthesis - Comprehensive …

Before the Chichibabin reaction, only on the pyridine ring was possible, which is difficult becausepyridine is an electron-poor aromatic compound and additionallyforms positive charged pyridinum ions, which further decrease theprobability of an electrophile attack. The positions in thepyridine system attacked by the electrophiles are the 3rd and the5th position.

The Chichibabin reaction is a method forproducing 2- derivatives by the reactionof pyridine with . It was reported by in 1914.

Hantzsch Dihydropyridine (Pyridine) Synthesis
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  • Pyridine synthesis - Organic Chemistry Portal

    The Chichibabin pyridine synthesis ( CHEE -chee- BAY -been ) is a method for synthesizing pyridine rings

  • Pyridine synthesis - Organic chemistry

    Chichibabin Pyridine Synthesis

  • Hantzsch pyridine synthesis - overview - ChemTube3D

    The Chichibabin pyridine synthesis ( CHEE -chee-bay-been ) is a method for synthesizing pyridine rings

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Hantzsch pyridine synthesis - Duration: ..

Pyridyl alcohols (e.g., 1, ) represent a unique class of picoline derivatives, which has proven broadly useful in the synthesis of ligands for the enantioselective hydrogenation of unactivated olefins (e.g., F, ) or for Pd-catalyzed allylic substitution reactions (e.g., G). Additionally, pyridyl alcohols have been found to self assemble in the presence of certain metal salts to form double-stranded helicates (e.g., H). As such, methods that provide direct access to alkylated variants of pyridyl alcohols would be highly valuable. An attractive option to achieve the direct alkylation of pyridyl alcohols would be to employ an alkylative variant of the Chichibabin reaction, which has been previously used in the direct alkylation of pyridines.

Synthesis of Pyridine derivatives by conden

To better understand the mechanism and explore the scope of these direct alkylation processes, a series of experiments, as outlined in –, was undertaken. Pyridyl alcohol 1 was treated with n-BuLi (1.0 equiv), followed by s-BuLi (1.1 equiv) as the nucleophile. The product, containing a s-butyl group at C(6) (15, ), was isolated in 63% yield, which suggests that, in principle, only 1.0 equivalent of the nucleophile is required. Therefore, for cases where a precious alkyl substituent is required, n-BuLi could be employed as the sacrificial base.

Not to be confused with Chichibabin pyridine synthesis

The pyridine heterocycle has emerged as an important structural motif in complex natural products, pharmaceuticals and in designer ligands for catalysis. The efficient preparation and study of pyridine-containing molecules depends on general and direct methods for the functionalization of pyridines and their corresponding picoline derivatives. Not surprisingly, numerous approaches have been established for the direct C(2) and C(6) functionalization of the pyridine nucleus, which include the introduction of heteroatoms (e.g., the Chichibabin reaction), as well as the installation of halogens and carbon substituents (e.g., using deprotonation/functionalization or the Minisci process)., However, several unmet challenges are inherent in the direct C(6) functionalization of picoline derivatives (e.g., A, ). These challenges include competing functionalization at C(4) (e.g., via C), as well as lateral functionalization of the picoline group. This latter competing process, which may be initiated by deprotonation of the pseudo-benzylic position (see E), plagues many attempts to directly functionalize picoline derivatives. In many cases, competing deprotonation leads to a lack of productive reactivity (e.g., via E) or decomposition (e.g., via D).

Pyridine - Synthesis & Reactions ..

The preparation of substituted pyridines by thermal cyclo-condensation of aldehydes and ammonia by passing aldehydes and ammonia over a contact catalyst such as is generally known as the Chichibabin pyridine synthesis. Besides aldehydes, ammonia gas also reacts with acetylene or acetonitrile over a heated contact catalyst to give pyridine derivatives. This reaction also takes place with aliphatic and aromatic ketones, α,β-unsaturated aldehyde, and keto acids. Presently, this reaction has been used to the syntheses of pyridine and collidine derivatives.

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