Medium-sized heterocycles

Free-radical syntheses of medium-size heterocycles 99T9349. 

The synthetic potential of such transformations for the preparation of medium-size heterocycles has been discussed elsewhere. It is generally accepted that the reaction between thiirene dioxides and enamines is a stepwise (nonconcerted) thermal [2 + 2] cycloaddition. However, a concerted [4 + 2] cycloaddition, in which the lone pair of the enamine nitrogen atom participates, cannot be excluded. 

Reductive cleavage of the N-N bond in bicyclic systems containing a ring junction hydrazine subunit presents a facile route to medium-sized heterocycles containing two or more nitrogen atoms and the subject was duly covered in CHEC-II(1996) <1996CHEC-II(8)747>. No substantial progress has been reported since its publication. 

Tanaka and Ohno developed the palladium(0)-catalyzed cyclization of bromoallene 222 bearing a sulfonamide for the synthesis of medium-sized heterocycle 223 (Scheme 37).48b In this reaction, bromoallene acts as an allyl dication equivalent 224, and two different nucleophiles can be introduced regioselectively. The intramolecular nucleophilic... 

This review will focus on the use of MCR approaches to cyclic peptides, cyclic peptidomimetics, or cyclic pseudopeptides, including small or medium-sized heterocycles as mimics of peptide motifs and macrocycles with amino acid or peptide moieties. 

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after... 

The two-carbon ring expansion which involves the [2 + 2] cycloaddition of enamines of cyclic ketones with electron-deficient acetylenes followed by thermal rearrangement of the resulting fused cyclobutenes (see Section II.E) has been successfully used in the synthesis of medium-size heterocycles. Examples include the preparation of compounds 407246, 408247 and 409248. 

A brief survey of a few medium-sized heterocyclic compounds (53) showing interesting conformational aspects ends this section. The cis.cis (27) and trans,... 

Metal-mediated synthesis of medium-sized heterocycles 00CRV2963. 

Synthesis of medium-sized heterocycles by the ring-closing metathesis reaction 00AG(E)2079. 

To demonstrate the versatility of this process and to provide a relevant model study for the synthesis of 1, we investigated an extension to medium-sized heterocycles. Thus, the diastereomeric silyl ethers 8a-b were selected to test this application by generation of the corresponding 9-membered oxacyclic dienes (Scheme 3). The preparation of 8a-b began with the reduction of pyruvic aldehyde dimethoxy acetal with NaBH4 in MeOH/THF to afford hydroxy acetal 2 (84%). Alkylation of the sodium salt of 2 with propargylic bromide afforded 3 (85%). Conversion of 3 to 5 was achieved by alkyne iodination followed by a c/s-reduction of... 

The cleavage of the N—N bond in bicyclic systems containing bridgehead hydrazine presents a facile route to medium-size heterocycles containing two or more heteroatoms. 

There are very few examples in the literature of fully saturated bicyclic selenonium ions with selenium as the bridgehead atom. The selenonium salts (33) and (34) are used as precursors for the syntheses of medium sized heterocycles containing a selenium atom. 

Neat exploitations of this process, include the synthesis of medium-sized heterocycles as products of a three stage sequence involving addition of hydroxide to w-iodoalkyl thiazolium salts, ring-opening and then reclosure by intramolecular S-alkylation, illustrated below for the formation of an eight-membered ring, " and the introduction of sulfur to the imidazole 2-position using phenyl chlorothionofor-mate. ... 

R. S. Glass (ed.) Conformational Analysis of Medium-Sized Heterocycles, VCH, New York, 1988. 738... 

The examples in Scheme 28 further demonstrate the feasibility of the construction of medium-sized heterocycles, hi these cases the endo-type cyclization is favored both by steric and by electronic factors. ... 

Quite a number of variations of this process have been reported in the past, for example, for the synthesis of medium-sized heterocycles.f" - ... 

Ohno H, Hamaguchi H, Ohata M, Kosaka S, Tanaka T (2004) Palladium(0)-catalyzed Synthesis of Medium-Sized Heterocycles by Using Bromoallenes as an Allyl Dication Equivalent. J Am Chem Soc 126 8744... 

Chloroacetamides of aminoalkyl derivatives of electron-rich aromatics 17, such as phenols, anisoles, or electron-rich heterocycles, easily dechlorinate and offer a useful entry to new medium-sized heterocycles (e.g., apogeissoschizine 18), according to Scheme 8.6a [6]. This is another example of the photochemical access to complex structures, that has been conveniently extended to macrocycle 19 (Scheme 8.6b), as well as to the reaction of W-alkylphthalimides [6]. 

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