Syntheses from Acyclic Fragments

The alkylthiodi-imide 71 reacts with ethoxymethylenemalononitrile at 140°C to give a dimethylcyanotriazolopyridine (94JCS(P1)825). 

A vinyl ether and an aryl hydrazide react to give compound 72 (83JHC1657). A large number of compounds have been made from a,P-unsaturated nitriles. Crotononitriles react with A-acetylcyanoacetohydrazide and with cyanocinna-monitrile to give compounds such as 73 (91GEP3926770), and compound 74 (90JOC2259), respectively. 

In all syntheses of [ 1,2,4]triazolo[4,3-a]pyridines it should be remembered that electron withdrawing substituents on the pyridine ring can cause Dimroth rearrangement of the initially formed compounds into derivatives of [l,2,4]tria-zolo[l,5-fl]pyridines (see Section B.2.c). 

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Numerous 1,4-oxazepines and 1,4-thiazepines have been synthesized mainly for biological and pharmaceutical purposes. A multitude of synthetic procedures are frequently used and well known by many chemists. In this part, we try to summarize the most important methods for their synthesis. Most of the intermediates during the synthesis are isolated before the cyclization, so these procedures can be classified as occurring via acyclic fragments. These procedures will be discussed in the following section. First, we review the synthesis from two fragments without the isolation of the intermediates. 

The highly stereoselective synthesis of 2,3-fr,ms--3-hydroxytetrahydropyran and 2,3-/ra r-3-hydroxyoxepane was achieved by the Sml2-induced reductive intramolecular cyclization from acyclic compounds having an aldehyde and a /3-alkoxyacrylate fragments <2002CL148>. Based on this reaction, new effective iterative syntheses of trans-fused 6,6,6-tricyclic, 6,7,6-tricyclic, and 6,7,7,6-tetracyclic ethers were developed <2002T1853>. 

Synthesis from fluorine-containing acyclic fragments. 

Synthesis of Fluoroall loxazoles and Fluoroall lbenzoxazoles from Fluorine-Containing Acyclic Fragments... 

A brief communication has recently been published [417] on the total synthesis of steroid compounds from BD fragments in which ring D is formed from acyclic precursors and is not introduced in the finished state, as in the preceding syntheses of this section (Scheme 83). The general route of the synthesis is close to that for the preparation of equilenin analogs described in Chapter II (Scheme 31). 

Evidently, an increase in steric hindrance around the reduced fragment requires the presence of ammonium fluoride in the reaction mixture. It should be noted that potassium fluoride has no effect. It is highly probable that ammonium fluoride is required for slow elimination of HF, which gradually desilylates the nitroso acetal fragment thus facilitating its reduction. As can be seen from Scheme 3.284, many reduction products are derivatives of unnatural amino acids. Since the initial nitroso acetals can be prepared by silylation of simple acyclic AN, possibilities have been opened for the synthesis of unnatural amino acids from available AN. 

Fragmentation reactions may be used to prepare cyclic or acyclic alkenes from cyclic precursors. The stereochemistry of the alkene can be set up by controlling the relative stereochemistry of the cyclic substrate, a process that is normally relatively easy. The ketone 35, for example, an intermediate in a synthesis of juvenile hormone, was obtained stereospecifically from the bicyclic compound 33 using two successive... 

Recently, Carreira and coworkers have utilized CIC Iz in their U-4CR for the rapid synthesis of the core fragment of Orodin alkaloid Massadine (252, Figure 7.6), which was isolated from Stylissa aff Massa [91]. Reaction of norbomenone (9v), 2,4-dimethoxy benzylamine (DMB-NH2, 6y), p-TsOH, and Iza provided the acyclic Ugi product 256 in a 79% yield. Removal of DMB group, Boc protection, and reduction, followed by treatment of -amylnitrile afforded the IV-acylbenzotriazole intermediate 257. Borohydride reduction of 257 provided alcohol 258. After several steps, the suitably substituted o-ring 259 of Massadine (252) was provided (Scheme 7.79) [91]. 

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