Cycloaddition reactions generation protocols

Dipolar cycloaddition of alkenes with carbonyl ylides generated in situ is a versatile method for tetrahydrofuran synthesis. The synthetic potential of such transformations has been reviewed <2005JOM(690)5533, 2003BMI6-253>. In addition, the stereoselective [3 + 2] annulation of allyl silanes has become a reliable protocol for the synthesis of tetrahydrofurans as demonstrated in several total syntheses . Such a [3 + 2] annulation, for example, affords the tetrahydrofuran product 11 as a single stereoisomer (Scheme 15) <2002OL2945>. Lanthanide salts serve as efficient Lewis acid catalysts in similar [3 + 2] cycloaddition reactions . 

A traceless linker strategy for the synthesis of functionalised furans based on mesoionic isomiinchnones generated on solid support, was developed by Gallop et alP- The key step of this protocol takes advantage of an efficient [3+2] cycloaddition reaction with electron deficient acetylenes, followed by a thermally promoted cycloreversion reaction. 3- 7 As shown in Scheme... 

By considering the mild conditions required for the generation of the bisbenzyne species in such cycloaddition reactions, Wudl employed compound 146 as the bisbenzyne precursor in the synthesis of 6,8,15,17-tetraphenyl-1.18,4.5,9.10,13.14-tetrabenzoheptacene (147) (Equation 12.40) [80]. In comparison to Pascal s protocol, Wudl s method afforded the cycloaddition product, heptacene 147, in a much higher (22%) yield. 

Most recently. Alcaide et al. described the generation of a highly active 1,2-dipole TfgC = CHg in situ, which immediately reacted at room temperature with an azide to afford previously unknown 4-trifluoromethanesulfonyl-l,2,3-triazoles 136 and 137 through a stepwise [3-t-2]-cycloaddition reaction from simple starting materials (Scheme 4.55) [54]. Remarkably, this mild and powerful uncatalyzed protocol is highly regio- and chemoselective. This metal-free method was applicable not only to ahphatic azides but also to aromatic ones. While the reactions of... 

The reaction protocol was further developed by alterations to the chiral controlling element of the reaction (49). Use of the precursor 183 under the standard ylide generation and cycloaddition conditions gave a greatly improved diastereomeric excess of >95%, an endo/exo ratio 1 15 and an isolated yield of 62%, with A-phenylmaleimide as the dipolarophile. The improvement in the reaction was rationalized by both endo and exo attack of the dipolarophile to the same diastereomerically favored face of the conformationally restricted U-shaped ylide 184 (Scheme 3.52). 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

An additional advantage of the intramolecular protocol stems from the opportunity to prepare easily the required polyfunctional precursors via cobalt carbonyl stabilized propargyl cations. The approach based on the tandem utilization of Co-mediated alkylation and Pauson-Khand annulation was developed in Schreiber s studies to elaborate short pathways for the synthesis of polycyclic compounds. An example of the efficiency of this protocol is the two-step transformation of the acyclic precursor 409 into the tricyclic derivative 410. The cobalt-complexed acetal 409 was first transformed into the cyclooctyne derivative 411 via intramolecular reaction of the in situ generated propargyl cation 409a with the allylsilane moiety. Cyclooctyne 411 underwent smooth cycloaddition in the presence of carbon monoxide to give the target compound 410 with excellent stereoselectivity. 

Aldol reaction and alkylation of ketones at the a-position via enol silyl ethers (11) under neutral conditions are good examples [8]. Ortho-quinodimethane (15) is afforded at room temperature and undergoes [4 + 2] cycloaddition [10]. In contrast, the thermal ring opening of benzocyclobutane requires a much higher temperature (180-190°C) [11]. The fluorine-mediated Si—C activation protocol was the preferred method for the formation of tetrafluoro-para-quinodimethane (19), which then dimerizes to octafluoro-para-cyclophane (20) [12]. Azomethine ylide (22) can be generated from 21 byAgF catalysis and is used for heterocycles syntheses [13]. 

Hamper and co-workers employed a solid-phase protocol for the generation of a large library of 5-(trifluoroacetyl)imidazoles (200 compounds) using the reaction between munchnones and benzamidines. Storr and co-workers employed the cycloaddition of munchnones 338 and 339 with 2-phenylbenzazete 337 to craft 3//-1,3-benzodiazepines 340 and 341 (Scheme 4.10). Upon heating and... 

Recently, Iwasawa established a set of transition metal-catalyzed protocols for an efficient construction of N l-C2-fused polycydic indole skeletons via a cycloisomerization-cycloaddition domino reaction of alkynyl imines 172 [222-224]. It was shown that the latter substrates, upon activation with transition metal catalysts, such as W(0), Pt(II), and Au(III), generate reactive azomethine ylide intermediates 174 similar to 166 (Scheme 9.64). Interception of such yUdes with a variety of suitably substituted alkenes 17S via a [3 - - 2]-cydoaddition affords fused indole products 177 through a transient formation of the corresponding metallocarbenoids 176. Transformation of terminal alkynyl imines proceeds with a 1,2-H shift in the 176, whereas... 

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