Substitution saturated heterocycles

Heterocyclization by catalytic formation of N—Car bond to give indoles, amino-pyridines, and N-aryl-substituted saturated heterocycles 98ACR805. 

Chemical libraries of /3-turn mimetics, among them highly saturated pyrazino[l,2-tf]pyrazines, were synthesized and patented as biologically useful compounds <2001W02001/000210>. Solid-phase syntheses starting from substituted a,/3-unsaturated ester templates provided differently substituted saturated heterocyclic systems, among them saturated 2,4,8-trisubstituted-pyrazino[l,2- ]pyrazine-l,6-diones <2003W02003/013740>. 

The reactions of anilines with 1,5-dialcohols catalyzed by ruthenium catalyst, RuCl2 (Ph3)3, are important136 since N-substituted saturated heterocyclic products like piperidines, piperazines or morpholines can be obtained in one step with water as the only side product (equation 15). 

Synthesis of monotrifluoromethyl-substituted saturated heterocycles 00T3635. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Alternative precursors for the synthesis of NHCs are thiourea derivatives of type 3. The preparation of such thiones with a symmetrical substitution pattern is achieved by the reaction of a-hydroxyketones like 3-hydroxy-2-butanone with suitable 2-thiones (Fig. 3d) [31] or by reaction of a diamine with thiophosgene [32, 33]. Unsymmetrically substituted thiones 4 possessing a saturated heterocycle have also been described (Fig. 3e) [34, 35]. 

Because of their completely saturated heterocycle, leucoanthocyanidins, together with flavan-3-ols are referred to as flavans. Examples of flavan-3-ols are catechin (1.39) and gallocatechin (1.40). The gallo in the latter compound refers to the vic-tri-hydroxy substitution pattern on the B-ring. Unlike most other flavonoids, the flavans are present as free aglycones or as polymers of aglycones, i.e. they are not glycosylated. 

The chemical shifts of the CHj groups in monocyclic alkanes are given in Table 4.4. Each ring skeleton has its own set of shfit parameters. Rough estimates for substituted rings can be made with the substitution increments in Table 4.3. Table 4.5 presents chemical shifts for several saturated heterocyclics. 

In the second case, the chlorine on the heterocyclic ring is much more reactive towarc. nucleophilic substitution as the intermediate is stabilized by both nitrogen atoms and the benzer. ring is not disturbed. The saturated heterocycle (a piperazine) can be made to react once only as thr product under the reaction conditions is strictly the hydrochloride of the unreacted amino grour This is much more basic than the one that has reacted as its lone pair is conjugated with th heterocyclic ring. 

These shortcomings have been circumvented by using a heterocycle containing a double bond, as illustrated by the examples in Scheme 21. As was the case with the achiral systems (c/. Scheme 11), a mixture of regioisomers is obtained, but now the a-substitution product (10) predominates. The amount of y-substitution product (11) produced depends on the ring size, and may be as high as 30% of the product mixture for the dehydropiperidines.Nevertheless, the unwanted y-isomer (11) is destroyed chemose-lectively when the mixture is treated with hydrazine to remove the chiral auxiliary. Double bond reduction would then give the a-alkylated saturated heterocycle. 

The reaction proved to be quite flexible both electron-rich and electron-poor substituted benzanilides worked well, as did heteroaroyl anilides, saturated heterocycle anilides, and alkyl anihdes. The presence of competitive acidic a-hydrogens or of a,P-unsaturated acyl residues did not lead to good results. For greater diversity, the cyano group of the original aniline could be efficiently replaced by a tert-butyl ester or a dimethylamide. Cleavage from the resin was performed with GH2Gl2/TFA/triethylsilane (94 5 1, v/v/v). The product (603) was then dried in vacuo at 40 °C. 

The tetrahydopyran nucleus is found in many classes of secondary metabolites, and a variety of methods are now available for the synthesis of this saturated heterocycle.As one might expect, cyclization strategies to oxanes are manifold. However, relatively few of these approaches are able to generate heavily substituted tetrahydropyrans with complete stereocontrol. 

Amines caimot undergo the substitution and elimination reactions that alkyl halides undergo, because the leaving groups of amines are too basic. Protonated amines also cannot undergo the reactions that protonated alcohols and protonated ethers undergo. Amines are easily oxidized. Saturated heterocycles containing five or more atoms have physical and chemical properties typical of acyclic compounds that contain the same heteroatom. 

The dipole moments of furan (0.72 D) and thiophene (0.53 D) are smaller than those of the corresponding saturated heterocycles (tetrahydrofuran, 1.68 D tetrahydrothiophene, 1.87 D.) Many authors " seem to believe that, also in these cases, the direction of the dipole is from the heteroatom (positive pole) to the ring (negative pole) others, however, are of a different opinion. - The values of the dipole moments of 2- and 3-substituted thiophens and furans, however, seem to indicate that the latter authors... 

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