Cydization reaction with

The transformation of2-734 involves an initial generation of an organosamarium species 2-735 with subsequent nudeophilic addition to the lactone carbonyl. Presumably, a tetrahedral intermediate 2-736 is formed that collapses to yield the ketone 2-737. This reacts with Sml2 to give a ketyl radical 2-738, which undergoes an intramolecular 5-exo radical cydization reaction with the alkene moiety. The resultant... 

Intramolecular nucleophilic displacement reactions of aromatic nitro group by various nucleophiles include cydization reactions, which provide practical methods for the synthesis of a variety of heterocycles. 1 hope that the text of this review suggests a wide range of potential of this reaction in organic synthesis of various heterocycles. However, it is necessary to stress that some structural types described in this review could be prepared with similar, or even better yields by other methods. In spite of this, there are many heterocyclic systems for the synthesis of which the denitrocyclization strategy is a method of choice. 

For the formation of substituted THF rings (Route a, Scheme 8.1), Kishi developed a procedure based on the hydroxy-directed epoxidation of a y-alkenol [10]. Epoxidation of bishomoallylic alcohol 3 by TBHP/VO(acac)2 by this approach, followed by treatment of the intermediate epoxide 4 with acetic acid, gave the TH F derivative 5 of isolasalocid A (a 5-exo cydization Scheme 8.2) [11]. Further epoxidation of 5 (a y-alkenol) under the same conditions, followed by acetylation, afforded epoxide 6. For the synthesis of the natural product, the configuration of epoxide 6 had to be inverted before the second cydization reaction. Epoxide 6 was consequently hydrolyzed under acid conditions to the corresponding diol and was then selectively... 

The outcomes of intramolecular cyclizations of hydroxy vinylepoxides in more complicated systems can be difficult to predict. In a study of the synthesis of the JKLM ring fragment of dguatoxin, epoxide 44 was prepared and subjected to acid-mediated cydization conditions (Scheme 9.24) [114]. Somewhat surprisingly, the expected oxepane 45 was not formed, but instead a mixture of tetrahydropyran 46 and tetrahydrofuran 47 was obtained, both compounds products of attack of the C6 and C5 benzyl ether oxygens, respectively, on the allylic oxirane position (C3). Repetition of the reaction with dimsylpotassium gave a low yield of the desired 45 along with considerable amounts of tetrahydropyran 48. 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

Enantioselective variants of the rhodium-catalyzed reductive cydization reaction using both cationic and neutral complexes have been reported. When 5 mol % of [Rh(cod)2]2 SbF6 was reacted with 129a, MeEt2SiH, and chiral ligand 163 a 76% yield of 154a was achieved with 88% ee (Scheme 33) [97]. Other substrates gave 50-75% chemical yields and 77-89% ee [97,98]. 

Interesting octahydroacridines 2-860 have been prepared by Beifuss and coworkers by combining the condensation step with a rare intramolecular polar [4jt++2 jrj-cydization of a-aryliminium ions 2-859, obtained from anilines 2-857 by reaction with the oo-unsaturated aldehyde 2-858 (Scheme 2.191) [440]. The overall domino process seems to be stereoselective, since the formation of the two di-astereomers 2-860 can be traced to the use of the substrate 2-858 as a diastereom-eric mixture. 

Balme and coworkers reported on a procedure for the preparation of highly functionalized furans of type 2-940 (Scheme 2.210) [480]. Their approach is based on a nucleophilic Michael addition of propargyl alcohols 2-937 to alkylidene or aryl-idenemalonates 2-938, followed by a palladium-catalyzed cydization via the carban-ion 2-939. The reactions with propargyl alcohol led to the formation of only one di-... 

Myicene with its conjugated diene system readily undergoes Diels-Alder reactions with a number of dienophiles. For example, reaction with 3-methyl-3-pentene-2-one with a catalytic amount of A1C13 gives an intermediate monocyclic ketone, which when cydized with 85% phosphoric acid produces the bicyclic ketone known as Iso E Super [54464-57-2] (49). The product is useful in providing sandalwood-like and cedarwood-like fragrance ingredients (91). 

However, if there is a lower enetgy decomposition pathway available, then an alternative degradation reaction dominates. There is a growing body of evidence to suggest that cydization reactions to form small stable ring compounds are one such decomposition pathway, especially for polyamides containing monomers with four to six carbon atoms (77,78) (eq. 7). The first example of this is the formation of cyclic amines, which is the principal decomposition pathway in nylon-4,6 (in eq. 7, n = 1 and R = H) (79) this has also been observed in MPMD-containing polyamides (in eq. 7, n = 2,... 

Pyrrole, 2-acetyl-1 -(2-hydroxyethyl)-5-nitro-cydization, 4, 74 ipso substitution, 4, 243 Pyrrole, 2-acetyl-1-methyl-dipole moment, 4, 194 photocydization reactions with 2,3-dimethylbut-2-ene, 4, 269 Pyrrole, 3-acetyl-4-methyl-Vilsmeier-Haack formylation, 4, 222 Pyrrole, 2-acetyl-3-nitro-reduction, 4, 297 Pyrrole, acyl-basicity, 4, 207 isomerization, 4, 208 oximes... 

Cycloaddition Reactions. Isocyanates undergo cycloadditions across the carbon—nitrogen double bond with a variety of unsaturated substrates. Addition across the C=0 bond is less common. The propensity of isocyanates to undergo cydization reactions has been widely explored for the synthesis of heterocyclic systems. Substrates with C=0, C=N, C=S, and C=C bonds have been found to yield either 2 + 2, 2 + 2 + 2, or 2 + 4 cycloadducts or a variety of secondary reaction products (2). 

One of the first examples of radical cydization reactions in the total syntheses of indole alkaloids was Stork s approach towards ( )-gelsemine (55) [58] featuring a mixed acetal 6-exo radical cydization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cydization conditions led to the cii-fiised bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,P-unsaturated ester 119 was secured when the selenide underwent... 

A different approach towards shape-persistent macrocydes is macrocycle preparation under thermodynamic control, i.e. if the desired structure is the most stable under the given conditions and the cydization reaction is reversible, one might be able to obtain a single macrocyclic product in quantitative yield although the reaction starts with small building blocks [41, 42],... 

Substituted maleic anhydrides have been directly exdted, but sensitization may also be used. In some cases the first method is better, and in some cases the second. In an approach to merrilactone A, which is closely related to the earlier-mentioned synthesis (Scheme 6.30), 2,3-dimethylmaleic anhydride was employed as a starting material in a sensitized [2 + 2]-photocydoaddition to 1,2-dichlorethene [114]. The reaction of tetrahydrophthalic anhydride (120) with alkenols and alkynols was conducted by direct irradiation in a Pyrex vessel. As an example, the reaction with allyl alcohol is depicted. The exo-product 121 was the preferred product with the endo-product cydizing spontaneously to lactone 122 (Scheme 6.43) [115]. Other alkenols reacted similarly. 

Tandem radical addition/cydization reactions have been performed using unsaturated tertiary amines (Scheme 9.11) [14,15]. Radical attack is highly stereoselective anti with respect to the 5-alkoxy substituent of 2-(5f-J)-furanones, which act as the electron-deficient alkenes. However, the configuration of the a position of the nitrogen cannot be controlled. Likewise, tandem addition cyclization reactions occur with aromatic tertiary amines (Scheme 9.12) in this case, acetone (mild oxidant) must be added to prevent the partial reduction of the unsaturated ketone [14]. 

The N-terminal residue, i.e., the first amino acid in the sequence of a peptide, can be determined by reaction with phenylisothiocyanate. At neutral pH, this compound reacts with the a-amino group. After mild acid hydrolysis, the reaction product cydizes, releasing the terminal residue as a phenylthiohydantoin (PTH) derivative (the Edman degradation. Fig. 4-1). The derivative can be analyzed to determine its parent amino acid and its quantity. 

This section has been strong on thermodynamic control but weak on the more common kinetic control. This will be remedied in Chapter 35 where you will meet the most important cydization reaction of all—the Diels-Alder reaction. It is under kinetic control and there is a great deal of stereochemistry associated with it. 

Another interesting tandem Michael initiated sequence was developed in our laboratory by combining the conjugate addition of unsaturated alkoxides to alkylidene malonates with a palladium-mediated coupling reaction with an organic halide. In this cydization reaction, an organopalladium species acts as the electrophilic partner of the cydization. This reaction results in the trans addition of the organopalladium species and of the nucleophile across the unsaturation, and therefore, in overall difunctionalization of the unsaturated substrates [66,67]. 

Electrophilic aromatic substitution of 5-hydroxy-2,4-dimethoxy-3-methylaniline by reaction with the iron complex salts affords the corresponding aryl-substituted tricarbonyliron-cyclohexadiene complexes. O-Acetylation followed by iron-mediated arylamine cydization with concomitant aromatization provides the substituted carbazole derivatives. Oxidation using cerium(IV) ammonium nitrate (CAN) leads to the carbazole-l,4-quinones. Addition of methyllithium at low temperature occurs preferentially at C-1, representing the more reactive carbonyl group, and thus provides in only five steps carbazomycin G (46 % overall yield) and carbazomycin H (7 % overall yield). 

Furthermore, as described by Mori and coworkers, the domino aldol/cydization reaction of the (3-keto sulfoxide 2-422 with succindialdehyde (2-423) in the presence of piperidine at r.t. afforded the chromone 2-424 which, on heating to 140 °C, underwent a thermal syn-elimination of methanesulfenic acid to provide 2-426 in 22 % overall yield (Scheme 2.100) [227]. This approach was then used for the synthesis of the natural products coniochaetones A (2-425) and B (2-427) [228],... 

Coupling of the aminomethylindole 2-558 with acrolein in a Michael manner followed by a HWE reaction with phosphonates 2-560 afforded 2-561 which cydized under basic conditions to give the desired product 2-566 via the intermediates 2-562-2-565 in 55 % yield (Scheme 2.127). The reaction sequence was also conducted in a stepwise manner, resulting in a greatly reduced yield this dearly demonstrates again the advantage of domino strategies over conventional methods. 

The cydization reaction of unsaturated compounds with CO is one of the most attractive reactions in organic synthesis. Recently, mthenium complexes were shown to have outstanding potential for catalytic activity in these reactions. 

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