Cyclization, base-initiated

Simple acetylenic allylic alcohols can be cyclized easily by tarf-butoxide, and since this base initiates prototropic shifts the vinylic link may.be E or Z such cyclizations proceed via exomethylene furans similar to 15.65 If necessary, UV irradiation can effect both the isomerization of an to a Z-alkene and the cyclization, leaving only the final adjustments to be made chemically.66 In a variation, methoxide plays the role of leaving group allowing very good yields to be attained (Scheme 10).67... 

Base-initiated cyclization has also been achieved with trifluoromethyl amidines 792 where ring closure to 3,4-dihydroquinazoline-4-carboxylates 793 was accompanied by loss of fluorine <2000CC1883>. 

In cyclizations of this type the reaction can be governed by kinetic factors or by conditions favoring the formation of a thermodynamically more stable product. For example, the formation of the kinetically favored pyr-rolo[2,3-b]quinoxalines 52 with the endo-configuration takes place under basic conditions, while in the absence of a base initially both stereoisomeric adducts 52 and 53 are formed. In the course of the reaction, however, rearrangement of 52 into the thermodynamically more favored exo-adduct 53 occurs (Scheme 44) (81DOK384). 

The following syntheses of natural products were based on the use of substo-ichiometric quantities of Cp2TiCl to catalyze different cyclization processes initiated by homolytic epoxide opening. They have been classified according to the type of cyclization process employed. Section 4.4 has been reserved for the Cp2TiCl-catalyzed radical cyclization of 2,3-oxidosqualene due to the biological importance of this terpenoid and steroid precursor. 

In the case of the successful Ni(II) cyclization, the initial report (1964) indicated that the reaction could be carried out by irradiating with a 200 W tungsten lamp. It was later determined (in 1966) that, in contrast to the case of the metal-free dideoxybiladienes, light did not serve to activate this particular metal-dependent cyclization. Conversely, the presence of a base was found to be essential." As part of this 1966 study, it was also found that cyclization of the metal(II)dideoxybiladienes-ac in the presence of di-f-butyl peroxide afforded only small yields of a mixture of macrocycles. The above results led to the suggestion that the cyclization of metal(II)dideoxybiladienes-ac does not proceed via a free-radical mechanism. It was thus proposed that the initial reaction involved abstraction of a proton from the central (C(10)) methylene group of the dideoxybiladiene-ac. 

The absence of cyclization at an earlier stage is responsible for the unique property of these monomers in providing an easy and effective route to high polymers by aprotic base initiation. This contrasts with other synthetic routes which are mainly employed in preparing sequential polypeptides [40]. The behaviour of glycine in forming a cyclic hexa-peptide is not found with most other NCAs since the development of secondary chain structures in the tail of the intermediate precludes cyclization. 

Carretero and co-workers found that dqjrotection and cyclization of the vinyl-sulfone 294 produced a 4 1 mixture of 2,3-cu-disubstituted pyrrolidine 295 and its tram isomer (Scheme 40). A/-Alkylation of the nuxture. with 3-chloro-2-chloro-methylprop-l-ene followed by chromatogttqjhy led to isolation of the pure 2,3-c/s product 296, silylation and base-initiated cyclization of which gave indolizidine 297. Ozonolysis and elimination of the sulfone group yieldied another pivotal intermediate, the bicyclic enone 298. Reduction with L-Selectride afforded an inseparable nuxture of two diastereomeric alcohols 299 (9 1). Separation was accomplished only after dihydroxylation with osmium tetroxide and peracetylation of the resdting tetrols. The synthesis of ( )-241 was completed by hyc lysis of the m or tetraacetate 300. 

Dialkylative cyclization reactions have been used to prepare bridged, spiro, and fused bicyclic sulfoienes. Reaction of 3-alkyl- and 3-chloro-3-sulfolenes (124a-d) with 1,3-diiodopropane, in the presence of 2 equivalents of base, initially furnishes intermediate anion (125). Intramolecular alkylation then takes place either at the a-position to deliver the bridged product (126) or at the y-position for the fused bicycle (127) [25] (Scheme 6.37). 

A further example for a metal-initiated reaction sequence providing an indole-inspired NP-based complex scaffold was reported by Van der Eycken and coworkers [7]. In this case, a Ugi reaction provided the desired substrate for the sequence of cyclization reactions initiated by the activation of the acetylene with a gold catalyst. The Ugi four-component reaction employed the indole-carboxaldehyde 12, the nitrile 13, amine 14, and carboxyhc acid 15 and led to the formation of the intermediate 16. In the presence of a gold(I) catalyst, instead of the expected indoloazepinone that could be formed via an endo-dig cyclization, a tetracyclic spiroindoline 17 was formed diastereoselectively (Scheme 13.3). 

This small peak probably arises from the methine and methylene protons in sequences of cyclized monomeric units (see equation (3.15)). The spectrum of the coloured polymer also contains a small peak at 8.31 ppm, probably due to the imino protons at the ends of the cyclized sequences. The base-initiated colouration of polyAN probably proceeds as shown in equation (3.15). This mechanism would explain why polymers made using anionic initiators based on alkali metals, especially at relatively high temperatures, tend to be discoloured. 

A reaction called the Johnson polyene cyclization (based on the Stork-Eschenmoser hypothesis) converts triene A into the polycyclic molecule B. When first discovered, an initially formed carbocation at one end of the polyene reacted with a nearby alkene to form a ring containing a new cation. This reacted with another nearby alkene, etc. The reaction was plagued by low yields and formation of polymeric material and decomposition products. This transformation required many years to perfect and two improvements were the use of a cyclopentenol unit on the left to initiate the sequence, which became a cyclopentene unit, and an alkyne unit on the right to end the sequence by generating a methyl ketone. Briefly discuss why these two improvements helped the problems inherent to this reaction. 

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

An interesting illustration of a bielectrophile contributing two heteroatoms to the resultant five-membered ring is the 2-alkyl-2-chloro- (or fluoro-) sulfonylcarbamoyl chlorides (212). With methylhydrazine initial attack by the more basic nitrogen occurred on the carbamoyl chloride, and this was followed by base-induced cyclization to 1,2,3,5-thiatriazolidine derivative (213) (77JCR(S)238, 77JCR(M)2813). Other reactions of this type are discussed in Chapter 4.28. 

Based on these observations, it is likely that the mechanism involves initial formation of thione 3 (X = O or S), which is followed by tautomerization to 4 and cyclization to 5. Aromaticity drives the facile elimination of either H2O or H2S resulting in the thiophene product. 

A variety of l,2,3,4-tetrahydro-j8-carbolines have been prepared from 3-piperidone phenylhydrazone derivatives. Used initially to obtain pentacyclic derivatives (35) related to the yohimbe alkaloids, this route was later extended to the synthesis of tetracyclic compounds (36). l-Methyl-5,6,7,8-tetrahydro-j8-carboline (37) was prepared in low yield by heating cyclohexanone 2-methyl-3-pyridylhydrazone with zinc chloride, a synthesis probably based on the similar preparation of the tetracyclic compound 38 starting from the corresponding quinolylhydrazine. Abramovitch and Adams extended this approach to the cyclization of cyclohexanone 3-pyri-dylhydrazone (39) itself. The main product was 6,7,8,9-tetrahydro-8-carboline (40), a smaller amount of the j8-isomer (41) also being obtained. This provides a convenient and readily reproducible route to the otherwise difficultly accessible 8-carboline ring system. The favored attack at carbon-2 over carbon-4 of the pyridine nucleus... 

The biological activity of calicheamicin 4 (simplified structure) is based on the ability to damage DNA. At the reaction site, initially the distance between the triple bonds is diminished by an addition reaction of a sulfur nucleophile to the enone carbon-carbon double bond, whereupon the Bergman cyclization takes place leading to the benzenoid diradical 5, which is capable of cleaving double-stranded DNA." ... 

Altanserin (100) is a representative of the thiaquinazolinones. This serotonin antagonist is said to prevent gastric lesions. One method for preparation of this compound involves first preparation of isothiocyanate derivative 99, by reacting 4-fluorobenzoylpiperidine with 2-bromoethylamine and then converting the intermediate to the isothiocyanate with thionyl chloride and base. Condensation of 99 with methyl anthranilate (98) probably proceeds initially to a thiourea. Cyclization by ester-amide interchange leads to altanserin (100) [28]. 

The finding that the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28]. 

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