Heterocycle-bearing side chain

Sheremetev and co-workers employed diazo compounds of type 60, prepared from the corresponding amines in moderate yields as alternative excellent precursors for the preparation of side-chain-functionalized derivatives (Scheme 29). Several furazans bearing reactive groups or cyclopropyl or five-membered heterocyclic substituents have been prepared by standard procedures (99MI6). 

Unfortunately, complexes 39 and 40 are still more prone to decomposition than catalyst 16. Therefore, Grubbs sought to investigate a series of new ruthenium catalysts bearing NHCs with varying degrees of iV-heterocyclic backbone and aryl side chain substitution, and catalysts 16 and 30a were chosen as basic catalyst structures [57]. In 2009, complexes 41a-c and 42a-c were prepared to attempt to understand how the degree of substitution on the backbone influences catalyst activity and lifetime (Fig. 3.15). 

In 2008, Grisi et al. reported three ruthenium complexes 65-67 bearing chiral, symmetrical monodentate NHC ligands with two iV-(S)-phenylethyl side chains [74] (Fig. 3.26). Three different types of backbones were incorporated into the AT-heterocyclic moiety of the ligands. When achiral triene 57 was treated with catalysts 65-67 under identical reaction conditions, a dramatic difference was observed. As expected, the absence of backbone chirality in complex 65 makes it completely inefficient for inducing enantioselectivity in the formation of 58. Similarly, the mismatched chiral backbone framework of complex 66 was not able to promote asymmetric RCM of 57. In contrast, appreciable albeit low selectivity (33% ee) was observed when the backbone possessed anti stereochemistry. 

Histidine is characterized by a heterocyclic side chain known as imidazole. The imidazole group will bear a positive charge under physiological conditions. Histidine is the metabolic precursor to histamine, a potent inflammatory molecule. Antihistamines work by antagonizing the action of histamine. 

Cimetidine contains an imidazole ring comparable to histamine, a sulfur atom (thioether group) in the side-chain, and a terminal functional group based upon a guanidine (see Section 4.5.4). Ranitidine bears considerable similarity to cimetidine, but there are some important differences. The heterocycle is now furan rather than imidazole, and the guanidine has been modified to an amidine (see Section 4.5.4). A newer drug, nizatidine, is a variant on ranitidine with a thiazole heterocyclic ring system. 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

In intramolecular arylations, a new bond is created between two aromatic moieties of the same molecule or between an aromatic nucleus and an atom of a side-chain. Many intramolecular arylation reactions of homocyclic and heterocyclic aromatic halides have been studied mainly in view of their synthetic applications, and it is not always clear which mechanistic pathway is followed. The reaction may start with homolytic or heterolytic dissociation of the carbon-halogen bond and proceed by attack of the aryl radical or aryl cation on another part of the molecule. Electrocyclization followed by elimination of hydrogen halide is another possibility. Especially when heteroatoms such as nitrogen, sulphur or phosphorus are involved, the initial step may be a nucleophilic attack on the carbon atom bearing the halide atom. 

DAIB and BTIB oxidations of phenols proceed through aryloxyiodane 129 and/or aryloxenium ion 130 intermediates and are quite useful for the preparation of quinones, quinol ethers, and quinone acetals (e.g., Scheme 39) (88TL677, 92MI2, 93JCS(P1)1891, 01OR327). When phenols bearing nucleophilic side chains are used as substrates, such oxidations provide fertile ground for the assembly of heterocyclic structures. This can be accomplished by oxidative-cyclization reactions of different types. 

A similar type of cascade reaction has been carried out with cyclic alkenes bearing only one olefinic side chain to obtain substituted heterocycles via ruthenium-catalyzed ring closing-ring opening metathesis (RCM-ROM) reactions. The preparation of enantiomerically pure cis- or trans-a,a -disubstituted piperidines has been achieved in the same yield for the two diastereoisomers [35] (Scheme 17). This reaction has also been used as a key step for the synthesis of natural products [36-39]. 

The therapeutic potential of HENECA for the treatment of cardiovascular diseases, and the need for more selective A2a agonists prompted us to synthesize a number of new 2-alkynyl derivatives of NECA bearing hydroxyl, amino, chloro, cyano, and heterocyclic groups or substituted aromatic or heteroaromatic rings in the side chain [27,28]. 

Analogous reactions leading to heterocyclic compounds were carried out in the same years by Tundo and coworkers by reacting aromatic isonitriles with alkyl and sulfanyl radicals bearing a cyano-substituted side-chain. In the first example [17],... 

An interesting application of this oxidizing agent is in the formation of spiroisoxazolines from o-hydroxyarylacetoxime derivatives, as well as the more well-known transformation of 2-(l-hydroxyalkyl)furans to the pyranones. The cycloamination of an aromatic compound bearing a sulfonamide side chain provides access to A-heterocycles. 

Paclitaxel analogs bearing a side chain containing heterocyclic or cycloalkyl groups have also been shown to possess anticancer activity, and the enzymatic resolution of racemic mixtures of such intermediates has again been investigated at Bristol-Meyers Squibb [70]. Racemic ds-34 could be stereoselectively hydrolyzed by Pseudomonas cepacia lipase (Amano PS-30) immobilized on Ac-curel and led to high optical purities of the desired (3R,4R)-enantiomer 34 (Scheme 11). Contrary to the use of the free enzyme, the immobilization reduced the required amount of biocatalyst by a factor of 10. 

Several other research groups are actively contributing in this field of CcO model chemistry. Naruta et al. have reported tris(2-pyridylmethyl)amine Cu complex-linked iron meso-tetra-phenylporphyrin derivatives and well-characterized Fe—(O2)—Cu species that are similar to [( L)Fe -(0 )-Cu ]+ (Structure (7)). A CcO model developed by Casella and co-workers is a natural porphyrin derivative, in which a polybenziimidazole residue for the Cu coordination site is attached to the propionic acid side chain of the deuteroporphyrin. A new class of picket porphyrin, bearing covalently linked, axially placed tris(heterocycle) chelates for a copper ion, has been synthesized and characterized by Wilson and co-workers. ... 

Kita Y, Egi M, Okajima A, Ohtsubo M, Takada T, Tohma H (1996) Hypervalent iodine(lll) induced intramolecular cyclization of substituted phenol ethers bearing an alkyl azido side-chain - a novel synthesis of quinone imine ketals. Chem Commun 1491-1492 Kita Y, Egi M, Ohtsubo M, Saiki T, Takada T, Tohma H (1996) Novel and efficient synthesis of sulfur-containing heterocycles using a hypervalent iodine(lll) reagent. Chem Commun 2225-2226... 

The oxidation of phenol ethers containing the azido group as an internal nidogen nucleophile provides a useful methodology for the construction of nitrogen heterocycles [370-372], Kita and coworkers have reported an efficient synthesis of quinone imine ketals 308 from the substituted phenol ethers 307 bearing an alkyl azido side chain (Scheme 3.126) [371]. 

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