Cycloaddition direction

Azolotriazines can be formed by cycloaddition reactions between diazoazoles and various substituted alkynes. In order to determine the mechanism of these reactions, semi-empirical AMI, MNDO, and PM3 calculations were run <1999JMT103>. Depending on the nature of the alkyne partner, these condensations may be viewed either as [7+2] cycloadditions, directly forming azolotriazines, or as [3+2] cycloadditions forming spirobicyclic intermediates, which quickly rearrange to azolotriazines. 

The authors proposed mechanism, outlined in Scheme 9.19, was tested using a deuterium-labeling experiment. H-migration consistent with initial formation of a Pd-vinylidene was observed. The key intermediate of Buono s mechanism is a palladacyclobutane (125) resulting from [2 + 2]-cycloaddition. Direct C—C reductive elimination from intermediate 125 proceeds to give highly strained products (123), despite the apparent availability of a (l-hydride elimination pathway [39]. 

The valence isomerization of cyclooctatetraene to semibullvalene developed by H. E. Zimmerman may be rationalized in terms of an intramolecular cycloaddition. Direct formation of C-C bonds between C1-C5 and C4-C6 of a hexatriene unit seems to be the most probable reaction pathway. It should be noted that this photoreaction belongs to the rare examples of a gas phase photolysis useful for synthetic purposes. 

Cycloadditions. Direct cycloaddition of Me3SiCHN2 to Ai-sulfonylimines afford aziridines with high cij-selectivity. Due to stereoselective ring opening and replacement of the silyl group by a carbon chain offered by the products, synthetic potentials are indicated. 

C-alkylation, directed condensation, -cycloaddition, direction of -functionalization, — halogenation, directed nitration, direction of -ring opening, —... 

Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

The simplest of all Diels-Alder reactions cycloaddition of ethylene to 1 3 butadi ene does not proceed readily It has a high activation energy and a low reaction rate Substituents such as C=0 or C=N however when directly attached to the double bond of the dienophile increase its reactivity and compounds of this type give high yields of Diels-Alder adducts at modest temperatures... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Nitrile A-oxides, under reaction conditions used for the synthesis of isoxazoles, display four types of reactivity 1,3-cycloaddition 1,3-addition nucleophilic addition and dimerization. The first can give isoxazolines and isoxazoles directly. The second involves the nucleophilic addition of substrates to nitrile A-oxides and can give isoxazolines and isoxazoles indirectly. The third is the nucleophilic addition of undesirable nucleophiles to nitrile A-oxides and can be minimized or even eliminated by the proper selection of substrates and reaction conditions. The fourth is an undesirable side reaction which can often be avoided by generating the nitrile A-oxide in situ and by keeping its concentration low and by using a reactive acceptor (70E1169). 

The reaction of benzonitrile A-oxide with a- and )3-azidostyrenes (351) and (352) gave 3,5- and 3,4-diphenylisoxazoles (353) and (354), respectively, in good yields (74JOC1221). Clearly, the X function has a pronounced directional effect on this type of 1,3-cycloaddition... 

Concerted cycloadditions are observed with heterocyclics of all ring sizes. The heterocycles can react directly, or via a valence tautomer, and they can utilize all or just a part of unsaturated moieties in their rings. With three-membered rings, ylides are common reactive valence tautomers. Open chain 47T-systems are observed as intermediates with four-membered rings, and bicyclic valence tautomers are commonly reactive species in additions by large rings. Very often these reactive valence tautomers are formed under orbital symmetry control, both by thermal and by photochemical routes. 

Doubt (75ZN(B)822) has been cast on a number of claims for the formation of 2-azetin-4-ones from cycloaddition of activated isocyanates to acetylenes (70TL119). The simple 2-azetin-4-one (246) was not isolated or even detected directly at -50 °C in the photofragmentation of compound (245), but indirect evidence for its formation was the isolation of adducts (248 X = MeO, MeNH) in the presence of methanol or methylamine (75TL1335). The most convincing evidence for an isolable 2-azetin-4-one involves treatment of the... 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

Direct photochemical excitation of unconjugated alkenes requires light with A < 230 nm. There have been relatively few studies of direct photolysis of alkenes in solution because of the experimental difficulties imposed by this wavelength restriction. A study of Z- and -2-butene diluted with neopentane demonstrated that Z E isomerization was competitive with the photochemically allowed [2tc + 2n] cycloaddition that occurs in pure liquid alkene. The cycloaddition reaction is completely stereospecific for each isomer, which requires that the excited intermediates involved in cycloaddition must retain a geometry which is characteristic of the reactant isomer. As the ratio of neopentane to butene is increased, the amount of cycloaddition decreases relative to that of Z E isomerization. This effect presumably is the result of the veiy short lifetime of the intermediate responsible for cycloaddition. When the alkene is diluted by inert hydrocarbon, the rate of encounter with a second alkene molecule is reduced, and the unimolecular isomerization becomes the dominant reaction. 

One of the features of Diels-Alder reactions with most alkyl and aryl nitriles that has made them rather unattractive as dienophiles is the requirement of very high reaction temperatures Again, only when electron-withdrawing substituents are directly bonded to the nitnle function do [4+2] cycloaddition reactions occur at reasonably low temperatures [ 48, 231, 232] A high yield [4+2] cycloaddition was observed on reaction of 4,4-bis(trifluoromethyl) 1 thia-3-aza-l,3-butadienes with trifluoroacetonitrile at 150 °C [225]... 

Further variations on this methodology were explored in chemistry directed to the synthesis of antitumor antibiotic CC-1065 61. Intramolecular cycloaddition with concomitant loss of nitrogen transformed 62 into 63. Further manipulation gave 64 which served as a building block in the assembly of 61. 

The isomeric 4-iodopyrazole-5-carboxylic acid is cyclocondensed in a similar way. Introduction of the additional methyl group into the ring has no effect on the direction of cycloaddition 4-iodo-l,3-dimethylpyrazole-5-carboxylic acid forms only 5-lactones (Scheme 118). 

The parent TMM precursor (1), now commercially available, has played a pivotal role in the execution of many synthetic plans directed at natural and unnatural targets. Reaction of (1) with 2-(methoxycarbonyl)cyclohexenone (14, R=C02Me) in the presence of palladium acetate and triethyl phosphite produced the adduct (15) in near quantitative yield. This cycloadduct is a critical intermediate in the total synthesis of a hydroxykempenone (16), a component of the defensive substances secreted by termites (Scheme 2.5) [12]. In accord with a previous observation by Trost that unactivated 2-cyclohexenone reacts poorly with TMM-Pd [13], the substrate (14, R=Me) was essentially inert in the cycloaddition. 

The main strategy for catalytic enantioselective cycloaddition reactions of carbonyl compounds is the use of a chiral Lewis acid catalyst. This approach is probably the most efficient and economic way to effect an enantioselective reaction, because it allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires a sub-stoichiometric amount of chiral material. 

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

The author has been involved for quite a long time in the study of Lewis acid catalysis of 1,3-dipolar cycloaddition reactions. From his research group, a series of methodologies directed to the Lewis acid-mediated stereochemical and regiochem-ical control of 1,3-dipolar cycloaddition reactions has been reported this includes ... 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

By selection of conditions and catalyst, the intermediate hydroxyimine (11) can be directed to either (he hydroxy ketone (10) or amino alcohol (12), Over platinum oxide in methanol-acetic acid-water the amino alcohol forms, whereas over alkali-free Ra-Ni in methanol-water or over 10% Pd-on-C in methanol-water containing boric acid, the hydroxy ketones form in excellent yield. Nitrile oxide cycloadditions have been applied to five-membered ring syntheses (.50). 

Bicyclic ketone 13 is a pivotal intermediate in Corey s approach to the prostaglandins. Buried within 13 is the five-membered ring of PGF2a, albeit in an undeveloped form. It would appear that a particularly direct approach to the synthesis of 13 would involve a [4+2] cycloaddition reaction between substituted cyclopentadiene 15 and ketene. Unfortunately, however, ketene itself is not a suit-... 

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