1.3- Dipolar cycloaddition reactions intermolecular

Click chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various /weiido-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed... 

An interesting antibody-catalyzed intermolecular asymmetric 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide and N,N-dimethylacrylamide generating the corresponding 5-acylisoxazoline was observed (216). Reversed regioselectivity of nitrile oxide cycloaddition to a terminal alkene was reported in the reaction of 4-A rt-butylbenzonitrile oxide with 6A-acrylamido-6A-deoxy-p-cyclodextrin in aqueous solution, leading to the formation of the 4-substituted isoxazoline, in contrast to the predominance of the 5-substituted regioisomer from reactions of monosubstituted alkenes (217). 

Intermolecular Reactions Intermolecular 1,3-dipolar cycloaddition reactions of nitrones to olefins seem to be the most studied. They are widely used for the synthesis of different enantiomerically pure compounds, including biologically active ones. For example, two new glycosidase inhibitors have been obtained by the nitrone cycloaddition strategy (Fig. 2.32) (733). 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Alcaide and coworkers have reported in 2002 the synthesis of various types of racemic and homochiral 1,3,4-trisubstituted- or fused polycyclic (3-lactams (III and IV, respectively, Fig. 9) via intermolecular 1,3-dipolar cycloaddition reaction of 2-azetidinone-tethered nitrones with a variety of alkenes or alkynes [264]. 

Intermolecular cyclization reactions which involve 1,3-dipolar cycloaddition reactions 133... 

Numerous methods of preparing bicyclic systems from monocyclic precursors have been reported and four general strategies can be identified. These are (i) intermolecular cyclization reactions which do not involve 1,3-dipolar cycloaddition reactions (ii) intermolecular 1,3-dipolar cycloaddition reactions (iii) nonoxidative intramolecular cyclizations and (iv) oxidative intramolecular cyclization reactions. These four general methodologies are now considered. 

The cyclodehydration of 2-substituted-A/-acylthiazolidine-4-carboxylic acids yields bicyclic munchnones. This mesoionic ring system acts as a cyclic azomethine ylid and can undergo 1,3-dipolar cycloaddition reactions with dipolarophiles. A range of chiral pyrrolo[l,2-c]thiazoles have been prepared by this method both intermolecularly and intramolecularly. 

Modifying the aldehyde function in the pyrroles 1162 into 1,3-dipoles 1163 (nitrone) and 1167 (nitrile oxide) furnished tricyclic heterocycles 1164 and 1168 via intramolecular 1,3-dipolar cycloaddition reactions (Scheme 226) <2000T3013>. None of the isomeric bridged product 1165 is produced despite the preference for that regiochem-istry in the intermolecular reaction. Generated in situ (from the oximes 1166) nitrile oxides 1167 cyclized spontaneously to the dihydroisooxazole 1168 in quantitative yield at room temperature. 

A non-biomimetic synthesis of /J-(-)-horsfiline (57) has also been recently reported which was based on a thermal intermolecular 1,3-dipolar cycloaddition reaction as outlined in Scheme 7 [63J. The reaction of the optically active menthyl ester 67 acting as a dipolarophile, with the JV-methylazomethine ylide 68 (thermally generated in situ from sarcosine and formaldehyde) proceeded with n-facial diastereoselectivity to produce a chromatographically separable mixture of 69 and the unwanted diastereomer. Subsequent cleavage of the chiral auxiliary, followed by removal of the carboxylic acid group by the Barton radical method provided J7-(-)-horsfiline. 

Two concurrent reactions, in which either the acetylenic fragment at C-3 of the 1,2,4-triazine ring participates in an intramolecular [4+2] Diels-Alder ring-transformation reaction ( = 1), or diethyl acetylenedicarboxylate undergoes an intermolecular 1,3-dipolar cycloaddition reaction, leading to pyrrolo[2,l ][l,2,4]-triazines, have been described (Scheme 112) <2001MC19>. 

Dipolar cycloaddition reactions occurreadily even with non-activated dipo-larophiles, such as isolated alkenes. This contrasts with the Diels-Alder reaction, particularly for intermolecular reactions, in which an activated alkene as the dienophile is required. Like the Diels-Alder reaction, [3+2] cycloaddition reactions of 1,3-dipoles are reversible, although in most cases it is the kinetic product that is isolated. For the intermolecular cycloaddition of nitrile oxides or nitrones, two of the most frequently used 1,3-dipoles, to monosubstituted or 1,1-disubstituted alkenes (except highly electron-deficient alkenes), the oxygen atom of the 1,3-dipole becomes attached to the more highly substituted carbon atom of the alkene double bond. Hence the 5-substituted isoxazolidine 206 is generated from the cycloaddition of the cyclic nitrone 205 with propene (3.136). Reductive... 

Shea et al. investigated whether strain involved in alkenes affects reactivity and regiochemistry of the intermolecular 1,3-dipolar cycloaddition reaction [14]. Therefore, the addition of picryl azide (18) with a series of mono-and bicyclic olefins including frans-cycloalkenes and bridgehead alkenes was studied (Scheme 5). In the cases of czs-cyclooctene (16) and ci5-cyclononene (17), decomposition of the initially formed cycloadducts 19 and 20 followed... 

The preparation of 85, a structurally diverse analog of carbocyclic ribavarine (86), was reported using an intermolecular 1,3-dipolar cycloaddition reaction of cyclopentyl azide 84 with methyl propiolate [53]. 

The synthesis of biologically important trifluoromethyl-substituted diox-olanes has been accomplished via 1,3-dipolar cycloaddition reaction of an intermolecularly generated carbonyl yhde with an aryl aldehyde. For example, the reaction of methyl diazo(trifluoromethyl)acetate (25) with two equivalents of aryl aldehydes afforded dioxolanes 27,28 [71]. The diastereoselectivity of these reactions depends on the substituent present on the aryl aldehyde (Scheme 8). 

Kappe and co-workers have extended their intermolecular isomiinch-none cycloaddition reaction (see Scheme 26) to an intramolecular version to obtain the conformationally rigid polyheterocycles 206, which mimic the putative receptor-bound conformation of dihydropyrimidine-type calcium channel modulators [159]. The key step in the synthesis involves the regio- and diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of a dihydropyrimidine-fused isomiinchnone dipole. The diazoimides... 

Surprisingly, treatment of 1 with Ag20 does not decompose the diazo ester but rather leads to the silver pyrazolate 6. A related observation has been made recently [6], Similary, a thermally induced intramolecular 1,3-dipolar cycloaddition reaction generates pyrazole 7. This reaction mode is limited, however, to specific substitution patterns. In other cases, an intermolecular rather than the intramolecular [3+2] cycloaddition comes into play (see next section). 

Hart and Brew Baker have described the cyclization of 1,3- bis(diazopropane) to pyrazole by a concerted intermolecular 1,3-dipolar cycloaddition reaction. 

Synthetic Applications of Intermolecular 1,3-Dipolar Cycloaddition Reactions... 

The utility of y-alkylidenebutenolides is demonstrated in both intra- and inter-molecular [Rh2(OAc)4l-catalysed 1,3-dipolar cycloaddition reactions in CH2CI2 affording spiro[6,4]lactone moieties with the concomitant constmction of quaternary Spiro stereocentres. Furthermore, a convergent and versatile route for the formation of the (5,7) skeleton of molecules, isolated from the Schisandra genus, is reported. Computational studies provided the mechanism of the intermolecular [3 + 2]-cycloaddition between 2-diazo-l,3-ketoester and protoanemonin and rationalized the empirical observations. " ... 

A review of recent developments in 1,3-dipolar cycloaddition of nitrones with sila-, thia-, phospha-, and halo-substituted alkenes has been reported. A DFT study of solvent effects on the intermolecular 3-l-2-cycloaddition reaction of norbornadiene with 3,4-dihydroisoquinoline A(-oxide at 398.15 K indicated that the reaction proceeds via a synchronous concerted mechanism. Chiral imidazolidinone salts, in the absence of water, promote the 1,3-dipolar cycloaddition reaction of alanine-derived ketonitrones... 

The rhodium-catalyzed tandem carbonyl ylide formation/l,3-dipolar cycloaddition is an exciting new area that has evolved during the past 3 years and high se-lectivities of >90% ee was obtained for both intra- and intermolecular reactions with low loadings of the chiral catalyst. 

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