Pyridines tetra-substituted

Tri- or tetra-substituted pyridines were prepared in a one-pot Bohlmann-Rahtz het-eroannulation of ethyl (3-aminocrotonate and an alkynone, which involved a Michael addition-cyclodehydration sequence. The reaction proceeded within just 20 min under single-mode microwave heating conditions (Scheme 3.28)48. 

Sulfonylation of free sucrose with 3 equiv. of p-toluenesulfonyl chloride in pyridine affords the l, 6,6 -tri-tritosylated sucrose in moderate yield,151,152 accompanied by the 6,6 -di-substituted as well as penta- and tetra-substituted derivatives. Using the more bulky mesitylenesulfonyl chloride, the T,6,6 -tri-sulfonylated derivative was obtained in 55% yield.152 Direct regioselective 2-p-toluenesulfonylation of sucrose with 7V-(/>-toluenesulfonyl)imidazole has been reported.106... 

The next breakthrough was obtained when iridium was used instead of rhodium. This idea was inspired by results from Crabtree who had described an extraordinarily active Ir-tricyclohexylphosphine-pyridine catalyst that was able to hydrogenate even tetra-substituted C=C bonds. For the MEA imine hydrogenation very good ee values were obtained with an Ir-bdpp catalyst in the presence of iodide ions (ee 84% at 0°C) but the activity was disappointing. Turnover numbers (ton) of up to 10000 and tof numbers of 250/h (100 bar and 25 °C) but somewhat lower ee values were obtained with Ir-diop-iodide catalysts [10, 11], A major problem with these new Ir-diphosphine catalysts was an irreversible catalyst deactivation. 

Based on these results, we realized that the catafyst activity would be the critical issue. Therefore, F. Spindler, who was responsible for the project, was very much attracted 1 the results of Crabtree et aL who described an extraordinarily active Ir / tricyclohexylphosphine / pyridine catafyst that was able to hydrogenate even tetra substituted C=C bonds [11]. He decided to give iridium catafysts a try even though he was aware of their frist deactivation and... 

While the approaches utilizing pyridine derivates often appeared promising on paper, in reality, multiple substitution reactions, complex chemistries, and several important compromises were generally required to install the desired C2-, C3-, C4-, and C5-tetra-substitution pattern and furnish an appropriately functionalized 6-azaindole. A closer look at the electronic pattern for a typical pyridine ring revealed that the C3 and C5 positions are the most difficult to... 

The Bagley group later developed a mild, single-step variant of the reaction, wherein acetic acid or Amberlyst 15 ion-exchange resin was used to promote cyclodehydration at a lower temperature (50 C) to give 2,3,6-tri-and 2,3,4,6-tetra-substituted pyridines 181 with alkyl, aryl, heteroaromatic, heteroatom, and ester substituents in moderate to excellent yields. ... 

A number of new pyridines and derivatives with promising biological activity were prepared this past year. For example, a review of the 4,5,6,7-tetrahydro-thienopyridines describes their preparation and various modes of activity (14Mini Reviews in Medicinal Chemistry988). A set of tetra-substituted pyrazoles attached to pyridines at C-2 and C-6 were prepared to study their biological activity (Scheme 2) (14ARK407). 

Isodesmosine, a 1,2,3,5-tetra-substituted pyridinium amino acid, is found in the elastin matrix and is formed in patients suffering from COPD as such, it is of interest for drug discovery and diagnosis (14TL6343). Isodesmosine and desmosine can be prepared via a Pr(OTf) 3-catalyzed Chichib-abin pyridine synthesis (Scheme 7).These materials are sparingly soluble in water the synthesis of the pyridines was heavily influenced by the solubility of the starting materials, a lysine and aldehyde derivative, in the water methanol co-solvent. In fact, as methanol increased, the yield of the desired pyridinium decreased. 

The influenee of peripheral substituents at the phthalocyaninato moiety on the properties of the corresponding compounds was studied with a number of octa-substituted derivatives R PcM, R PcMLj and [R PcM(pyz)] (e.g. R = CH3, m = 8, M = Fe, L=py) [83]. Substituted mononuclear and bridged phthalocyaninatoiron pyrazine complexes R PcFe(pyz)2 and [R PcFe(pyz)] are accessible according to the procedure for the corresponding unsubstituted complexes [65]. With cobalt as central metal the tetra-substituted macrocycles R PcCo (m = 4 R = f-bu, NO 2) can be prepared. They coordinate with pyridine and substituted pyridines to form the adducts R PcCoL2 [84]. With pyrazine the binuclear complex (t-bu)4PcCo(pyz)CoPc(t-bu)4 and the oligonuclear [(N02)PcCo(pyz)]n can be isolated and characterized [84]. 

Due to the electron-withdrawing nature of the pyridinium substituent onto the macrocycle, [113-118] the oxidation waves of the mono-substituted porphyrin (two successive one-electron redox processes at +0.98 and +1.28 V/SCE) are anodically shifted as compared to those of the parent ZnOEP macrocycle (+0.68 and +0.94 V/SCE, respectively) [118]. This explains why only the mono-substituted derivative is obtained when the electrolysis is pCTformed at +0.70 V/SCE. The potential is not sufficient to oxidize the ZnOEP(py) macrocycle to give the respective radical cation allowing a second substitution by pyridine. As a result, an increase of the potential applied during the electrolysis can induce multi-substitutions of the ZnOEP macrocycle. In particular, Ruhhnann and coworkCTS showed that a judicious choice of the applied potential allows a perfect control of the degree of substitution on the ZnOEP ring. Eor instance, electrolyses performed at +0.94, +1.10, and +1.20 V/SCE allowed the formation of the di-, tri-, and tetra-substituted pyridinium ZnOEP macrocycles, respectively (ZnOEP(py)n", n = 2-4) [118-120]. Depending on the potential, it is also possible to synthesize preferentially either the 5,10-di-substituted or the 5,15-di-substituted porphyrins. 

Pyridine hydrochloride in pyridine is a mild reagent for the nucleophilic cleavage of a conjugated (but not necessarily strained) cyclopropyl ring furnishing /S-chloromethyl ketones. Photo-oxidation of mono- and di-substituted alkenes in the presence of iron (ill) chloride affords a-chloro-ketones whereas tri- and tetra-substituted alkenes suffer cleavage to form dichloro-ketones [equations (45) and (46)]." °... 

Prajapati et al. reported the reaction between enone oximes and 1,3-dicarbonyl compounds that generated tetra-substituted pyridines in good yields using InCl3 as catalyst without any solvent [216]. The authors proposed that the reaction proceeds via an initial Michael-type addition of the 1,3-dicarbonyl compound to... 

Fig. 8.97 InCb catalyzed synthesis of tetra-substituted pyridines.

Etherification. The reaction of alkyl haUdes with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraaHyl ether is formed on reaction of D-mannitol with aHyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional aHyl bromide, leads to hexaaHyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trim ethyl chi oro s il an e in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

Since the nitrogen in pyridine is electron attracting it seemed reasonable to predict that the trihalopyridynes would also show the increased electrophilic character necessary to form adducts with aromatic hydrocarbons under similar conditions to those employed with the tetra-halogeno-benzynes. The availability of pentachloropyridine suggested to us and others that the reaction with w-butyl-lithium should lead to the formation of tetrachloro-4-pyridyl-lithium 82 84>. This has been achieved and adducts obtained, although this system is complicated by the ease with which pentachloropyridine undergoes nucleophilic substitution by tetrachloro-4-pyridyl lithium. Adducts of the type (45) have been isolated in modest yield both in the trichloro- and tribromo- 58) series. 

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