Cyclization, points

For fatty acid biosynthesis, reduction after each condensation step affords a growing hydrocarbon chain. In the absence of this reduction process, the growing poly- -keto chain needs to be stabilized on the enzyme surface until the chain length is complete, at which point cyclization or other reactions can occur. The poly-fj-kelo ester is very reactive, and there are various possibilities... 

The Fischer cyclization has proved to be a very versatile reaction which can tolerate a variety of substituents at the 2- and 3-positions and on the aromatic ring. An extensive review and compilation of examples was published several years ago[3]. From a practical point of view, the crucial reaction parameter is often the choice of the appropriate reaction medium. For hydrazones of unsymmetrical ketones, which can lead to two regioisomeric products, the choice of reaction conditions may determine the product composition. 

Another issue of regioselectivity arises with meta-substituted arylhydrazones from which either 4- or 6-substitutcd indoles can be formed. Robinson has tabulated extensive data on this point[9]. A study comparing regioselectivity of cyclization as catalysed by HCl/EtOH and ZnClj was carried out for several m-substituted arylhydrazones of diethyl ketone[10]. The results given in Table 7.1 show some dependence on catalyst but mixtures are obtained under all conditions studied. 

The cyclization of pentaacetyl-o-gluconic thioamide with chloroacetone and of pentaacetyl-D-galactonic acid thioamide with phenacyl bromide give the corresponding 4-substituted 2-(D-galactopentaacetoxypentyl)-thiazoles (27) (660) but in low yield (23 to 27%) (Scheme 13). The products may be deacetylated in the usual way. These compounds are interesting from a pharmacological point of view. 

The employment of non-protic electrophiles for the foregoing type of cyclizations as illustrated in Scheme 8 has the particular merit of leaving a useful point of departure for further transformations. Comparable cyclizations of 2-allyl-3-aminocyclohexenones with mercury(II) acetate are preceded by dehydrogenation to the corresponding 2-allyl-3-aminophenol as shown in Scheme 9 82TL3591). The preferred direction of cyclization depends upon the nucleophilicity of the amino group. 

Electrocyclic reactions of 1,3,5-trienes lead to 1,3-cyclohexadienes. These ring closures also exhibit a high degree of stereospecificity. The ring closure is normally the favored reaction in this case, because the cyclic compound, which has six a bonds and two IT bonds, is thermodynamically more stable than the triene, which has five a and three ir bonds. The stereospecificity is illustrated with octatrienes 3 and 4. ,Z, -2,4,6-Octatriene (3) cyclizes only to cw-5,6-dimethyl-l,3-cyclohexadiene, whereas the , Z,Z-2,4,6-octa-triene (4) leads exclusively to the trans cyclohexadiene isomer. A point of particular importance regarding the stereochemistry of this reaction is that the groups at the termini of the triene system rotate in the opposite sense during the cyclization process. This mode... 

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

Alkylation in position 3 has a still more pronounced effect. The thiosemi carbazones (101) obtained here were prepared either from 3-methylisothiosemicarbazide hydroiodide or by methylation of thio-semicarbazones. Their cyclization was performed either by boiling in alcohol or by heating to the melting point (102). The presence of... 

The high yields of the end products and the absence of other reliable synthetic routes to 1,5-benzothiazepine, 1,4-dithiepin, and 1,5-dithiocin derivatives of the above structures (85KGS1443) make these cyclizations attractive from the preparative point of view. 

In the case of l-dimethylaminobut-l-en-3-yne no 4-methylpyrimidine was isolated because its boiling point is close to that of a side product, dimethylfor-mamide. The latter results from transamination of formamide by dimethylamine in the course of cyclization. The pyrimidines 156 were isolated and characterized as picrates (70ZOR1528). For easier isolation of pure 4-methylpyiimidine... 

Earlier studies [14,15] clearly reveal that there is a reaction between two polymers and that the extent of reaction depends on the blend ratio. As 50 50 ratio has been found to the optimum (from rheological and infrared studies) ratio for interchain crosslinking, the higher heat of reaction for the NBR-rich blend may be attributed to the cyclization of NBR at higher temperatures. There is an inflection point at 50 50 ratio where maximum interchain crosslinking is expected. Higher viscosity, relaxation time, and stored elastic energy are observed in the preheated blends. A maximum 50-60% of Hypalon in NBR is supposed to be an optimum ratio so far as processibility is concerned. 

From the point of view of general synthetic applicability, Table 10-6 shows clearly that there is no overall rationale in these cyclization reactions. The range of yields is enormous and, in addition, it is hardly possible to specify whether heterolytic or homolytic reaction conditions are preferred. 

Braverman and Reisman111 have found that addition of a carbon tetrachloride solution of bromine to bis-y,y-dimethylallenyl sulfone 20 at room temperature unexpectedly resulted in spontaneous and quantitative fragmentation of the sulfone, with formation of the cyclic a, /3-unsaturated sulfmate (y-sultine) 43a and the tribromo products 44 and 45 (equation 38). Analogously, treatment of the same sulfone with trifluoroacetic acid gives rise to y-sultine 43b. It is interesting to note that from a synthetic point of view it is not even necessary to prepare the diallenyl sulfone 20, since one can use its sulfinate precursor (equation 24) to obtain exactly the same results, under the same conditions. The authors suggested that the fragmentation-cyclization of sulfone 20 may take place by the mechanism depicted in equation 39. 

The previously outlined mechanistic scheme, postulating reversible propagation and cyclization, was simplified by neglecting the de-cyclization because in the very short time of the studied reaction the extent of de-cyclization is negligible. The rate constants appearing in the appropriate differential equations were computer adjusted until the calculated conversion curves, shown in Fig. 7, fit the experimental points. The results seem to be reliable inspite of the stiffness of the differential equations. 

A similar pre-orientation involving unsaturated carbon chains was operative on generating twelve-membered enediyne 23 and arenediyne lactams 24 [7]. The seco methylesters 21 and 22 were cleaved with LiOH, the corresponding carboxylic acids underwent cyclizations after activation with 2-fluoro-pyridinium tosylate 25 [8]. Dimerization products were found as by-products (<10%). It should be pointed out, that the lactamization succeeded in a single step in about 75% yield by treating the seco-methylesters 21 and 22 with Me3Al in refluxing methylene chloride. Obviously, the latter route was more convenient (Scheme 5). 

In both oxa- and aza-alkyne Prins cyclization an unexpected halide exchange with halogenated solvents presumably caused by the vinyl cation intermediates was observed [37]. From a synthetic point of view, it is important to use the correct combination of FeXs and X-containing solvent in order to avoid the undesired halide scrambling (Scheme 28). 

Fig. 6.—Log of the cyclization constant C for the lactoniza-tion of co-hydroxy acids vs. ring size. The point for n = 5 represents a minimum value. (Data from Stoll and Rouv. )...

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