Regioselective cycloaddition

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

The reactivity and regioselectivity of the cycloaddition of l-(A-phenacylidene)amino-1,2,3-triazoles with diphenyl nitrilimine (see Section 4.01.7.4) are examined on the basis of CNDO/2 calculations. The cycloaddition regioselectivity is HOMOjdipoie) controlled. The predominant orbital interaction shown in Figure 1 rationalizes the regioselective formation of 277-1,2,3-triazoles... 

Our initial interest in this area arose from the observation that the orbitals of the commonly accepted planar geometry of the parent nitrile ylide do not correctly account for the cycloaddition regioselectivities observed for these species. Thus, as shown by the examples in Fig. 14, the digonal carbon is the nucleophilic center of the molecules, whereas the HOMO of the planar species has the largest coefficient at the trigonal carbon, which should, therefore, be the more nucleophilic center of the molecule. However, full optimization of the geometry of nitrile ylide using the... 

Similarly, the noncomplementary C-2 - or C-4 addition of an electron-withdrawing substituent to the 1-oxa-1,3-butadiene serves to lower substantially the 1-oxa-1,3-butadiene lumo> accelerates its 4 ir participation in a LUMOdiene-controlled [4 + 2] cycloaddition reaction, maintains the endb-derived diastereoselectivity through the maintenance (C-4) or enforcement (C-2) of a large LUMO C-2 coefficient, and does not alter the observed [4 + 2] cycloaddition regioselectivity, although such substitution may decrease the magnitude of the difference between the O-l/C-4 LUMO coefficients (Table 5). 

A Benzenesulfony 1 aldimines have been shown to be more reactive than 7V-benzenesulfonyl ketimines (eq 2), and the complementary addition of a C-3 or the noncomplementary addition of C-2 and C-4 electron-withdrawing substituents substantially accelerate the Diels-Alder reaction and maintain the expected cycloaddition regioselectivity and exceptionally high endo diastere-oselectivity (eqs 3-5). ... 

In the oxazole system, the structural element of a bridged 2-aza-l,3-diene is present. Therefore, oxazoles are enabled to undergo Diels-Alder reactions with activated alkenes and alkynes. For example, acryhc acid (as an unsymmetrical activated dienophile) adds to the oxazole 13 to give the product 14 of a (4 + 2)-cycloaddition regioselectively. The Diels-Alder adduct 14 can be transformed to the pyridine derivative 15 by acid-catalyzed dehydration. 

Spiteri C, Moses JE (2010) Copper-catalyzed azide-alkyne cycloaddition regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles. Angew Chem Int Ed 49(l) 31-33 Agalave SG, Maujan SR, Pore VS (2011) Click chemistry 1,2,3-triazoles as pharmacophores. Chem Asian J 6(10) 2696-2718... 

However, its implementation in tandem intramolecular cycloadditions could expand the range of oxadiazoles that participate in the reaction cascade, extend their use to unsymmetrical dienophiles and oxadiazoles, control the cycloaddition regioselectivity, and increase the utility of tandem Diels Alder/l,3-dipolar cycloaddition reactions of such heterocyclic azadienes [196]. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

Frontier molecular orbital theory correctly rationalizes the regioselectivity of most 1,3-dipolar cycloadditions (73JA7287). When nitrile ylides are used as 1,3-dipoles, the dipole... 

Photochemical [2 + 2] cycloaddition is a powerful way to produce cyclobutanes, which, in turn, are reactive synthesis intermediates. N-Methylpyrrole adds aldehydes via [2 -I- 2] photocycloaddition to give transient oxetanes with high regioselectivity Ring-opening produces 3-(oi-hydroxyalkyl)pyrroles which are oxidized easily to 3-arylpyrroles, such as 3-BUTYROYL-l-METHYL-PYRROLE. With a special apparatus, ethylene is conveniently added to 3-methyl-... 

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 ... 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

The regioselectivity of 1,3-dipolar cycloadditions can also be analyzed by MO calculations on transition-state models. For example, there are two possible regioisomers from the reaction of diazomethane and methyl vinyl ether, but only the 3-methoxy isomer is formed. 

Fluorinated allenes are especially reactive in cycloadditions because of their highly strained double bonds [118, 119] 1,1-Difluoro- and 1-fluoroallene readily undergo both [2+2] and [4+2] cycloadditions [118 124] (equations 50-52) Exten sive studies of stereochemistry and regioselectivity show that cyclobutane forma-... 

Cycloadditions ot diazomethane with fluonnated cyclobutenes provide insight into those factors that govern the reactivity and regioselectivity of such reactions Although 3,3,4,4-tetrafluorocyclobutene undergoes reactions at ambient temperature in 5 min [77, 72], complete reaction with the less reactive perfluorocyclobutene requires 14 days [7J] (equation 8). Note also the regioselectivity observed in the reaction of diazomethane with 3,3-difluorocyclobutene [14] (equation 9)... 

The regio- and stereoselectivities of cycloadditions of trifluoroacetonitrile oxide, which is generated m situ by treatment of the tnfluoroacetohydroxamyl bromide etherate with tnethylamine in toluene (equation 31), have been determined in a senes of studies by Tanaka [55, 36, 37, 5 ]. The highly reactive nitnle oxide reacts regioselectively with a variety of activated terminal alkenes and alkynes (equations 32 and 33)... 

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

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