Unsaturated heterocycles, synthesis

Small unsaturated rings are usually very reactive undergoing ring opening in a number of ways, and this characteristic has been utilized in heterocyclic synthesis. In their role as dienophiles or dipolarophiles, the initial cycloaddition is usually followed by a valence tautomerism resulting in a six-membered or larger ring system. Several examples exist, however, where this does not occur, and these are described below. 

Heterocyclic derivatives such as 59 provide a convenient route to the synthesis of many cyclic germanium compounds87. For instance, photolysis of 59 in the presence of alkynes 60 or 61, or allenes 62, produces the unsaturated heterocyclic compounds 63 or 64, respectively. 

In 1993, we reported that various unsaturated heterocycles can be alkylated with Et-, wPr- and nBuMgCl in the presence of optically pure (EBTHI)ZrCl2 (3a) or (EBTHI)Zr-binol (3b) to afford the derived unsaturated products in >90% ee (cf. 5 6, Scheme 2) [4a]. Many of the simpler five- and six-membered starting materials are available commercially or can be prepared by established procedures. In contrast, catalytic enantioselective reactions involving unsaturated medium ring hetero cycles were not a trivial undertaking the synthesis of these olefinic substrates, by the extant methods, was prohibitively cumbersome. 

Enantioselective Synthesis of Unsaturated Heterocycles by Tandem Catalytic RCM-Catalytic Kinetic Resolution... 

The chemistry described in this review article demonstrates the impressive positive influence that catalytic RCM has had on our research in connection to the development of other catalytic and enantioselective C-C bond forming reactions. There is no doubt that in the absence of pioneering work by Schrock and Grubbs, the Zr-catalyzed alkylation and kinetic resolution would be of less utility in synthesis. The number of unsaturated heterocyclic and carbocyclic substrates available for Zr-catalyzed asymmetric carbomagnesation would be far more limited without catalytic RCM. 

The reactivity and the synthesis of the fully unsaturated heterocycles compared to their partially or fully saturated members have been examined and developed in detail. The literature is mostly associated with ring synthesis, and a great deal of effort has been devoted over the last decade to develop various strategies and tactics for the preparation of these systems. Reactions in Section 11.04.9 are classified strictly according to the number of atoms in the... 

Macromers are then short polymers, which contain an active end group. This end group can be a site of unsaturation, heterocycle, or other group that can further react. Macromers are usually designed as intermediates in the complete synthesis of a polymeric material. These macromers can be introduced as side chains (grafts) or they may serve as the backbones (comonomer) of polymers. The macromers can also act as separate phases. 

Most recent studies indicate that ARCM can be used to synthesize small and medium ring N-containing unsaturated heterocycles in high yield and with excellent ee through catalytic kinetic resolution and asymmetric synthesis [19]. As the representative data in Scheme 10 illustrate, levels of enantioselectivity can vary depending on the nature of the arylamine (compare 44 to 46). As the synthesis of 48 indicates (cf. Scheme 10), the facility and selectivity with which medium ring unsaturated amines are obtained by the Mo-catalyzed protocol is particularly noteworthy. 

After the failure of the direct synthesis of the completely unsaturated heterocycle 34, an attempt was made to synthesize the partially saturated cyclopenta[t]-l, 2-diazcpine, which then could be dehydrogenated to the 5,6-diazaazulene 34. However, this approach by starting with a 1,2-diazepine ring 36 (made successfully by following published method) and its [3+2] palladium-catalyzed cycloaddition with allyl chlorosilane 35 to the bicyclic diazepine 37 failed (Scheme 8). 

Perfluoro-2-methyl-2-penten-3-yl isothiocyanate, which was prepared from perfluoro-2-methyl-2-pentene and KSCN in benzonitrile in high yield by direct substitution of fluorine, is a stable and versatile educt for heterocyclic synthesis. This a,p-unsaturated isothiocyanate reacted with enamines, such as 1-methylindole and 2-methyl-1-morpholino-l-propene, to yield 2-(l-methylindol-3-yl)-perfluro-4,5-dihydro-5,5-dimethyl-4-ethylidene-l,3-thiazole and its analogue in fair yield. [95H1015]... 

The disconnection approach to synthesis essentially involves working backwards from a target compound in a logical manner (so-called retrosynthesis), so that a number of possible routes and starting materials are suggested. This approach has been applied mainly to alicyclic, carbocyclic, and saturated heterocyclic systems. Retrosynthetic analyses are presented in this text not as an all-embracing answer to synthetic problems, but rather as an aid to understanding the actual construction of unsaturated heterocycles. 

Another approach to the synthesis of condensed azine derivatives (84UK1648 85KGS1011) is based on the ability of a number of azine derivatives to undergo diaddition reactions with nucleophiles. When bifunctional nucleophilic reagents are used, these additions result in the formation of cyclization products. In all these reactions the tetrahydro analogues of the fully unsaturated heterocyclic systems are obtained. 

RCM has become a major approach to the synthesis of partially unsaturated heterocycles with five-membered and larger rings (Scheme 67) <2004CRV2199>. 

The methods discussed in Section 4.2.1.4 can also be used in the synthesis of partially unsaturated heterocycles. 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

BBN-H tolerates many functional groups, and this, coupled with its high regioselectivity, allows the clean synthesis of a number of functionalized organoboranes e.g. equation 26), including many derived from unsaturated heterocyclic compounds. It also shows impressive stereofacial selectivity in the hydroboration of cyclic alkenes (e.g. equations 27-29), - and sometimes in the cases of acyclic alkenes. ... 

Optically pure 2,3-dihydropyrroles are important unsaturated heterocyclic compounds because of their application as chiral building blocks in the organic synthesis and the total synthesis of natural products. However, the asymmetric organocatalytic synthesis of chiral 2,3-dihydropyrroles is scarce. Highly diastereo- and enantiose-lective syntheses of 2,3-dihydropyrroles 14 by the base catalyzed asymmetric... 

Nitriles, a,]S-unsaturated, in synthesis of heterocycles 83H(20)519. Nitroalkenes in heterocyclic synthesis 86CRV751, 86H(24)2645 ... 

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