1.3- dipolar cycloaddition reactions with carbonyl ylides

Suga et al. (197) reported the first stereocontrolled 1,3-dipolar cycloaddition reactions of carbonyl ylides with electron-deficient alkenes using a Lewis acid catalyst. Carbonyl ylides are highly reactive 1,3-dipoles and cannot be isolated. They are mainly generated through transition metal carbenoid intermediates derived in situ from diazo precursors by treatment with a transition metal catalyst. When methyl o-(diazoacetyl)benzoate is treated with A-methylmaleimide at reflux... 

It is well known that di- and tetrahydrofurans can be obtained by inter- and intramolecular 1,3-dipolar cycloaddition reactions of carbonyl ylides with alkynes and alkenes. This methodology has also been shown to be of value in the preparation of a furanophane <92TL57>. 

The asymmetric induction on the 1,3-dipolar cycloaddition reaction of carbonyl ylides has also been studied using chiral dipolarophile. The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)diazoacetophenone 89 with enantiomerically pure vinyl sulfoxides 103 afforded 4,10-epoxybenzo-[4,5]cyclohepta[l,2-c]furan-3,9-dione 105, in good or moderate yield with complete regioselectivity [113]. The endo stereoisomer 105a is favored with respect to the exo isomer 105b and interestingly, high diastereoselectivity and complete enantioselectivity have been achieved (Scheme 32). 

Suga and coworkers reported utility of a Yb(OTf)3-PyBOX complex in 1,3-dipolar cycloaddition reactions of carbonyl ylide generated using Rh2(OAc)4 [71, 72]. As shown in Scheme 13.26, the Yb(OTf)3/Ph-PyBOX complex promoted the reaction of 2-benzopyryrium-4-olate with 3-acryloyl-2-oxazolidinone in endojexo = 12 88,... 

The l,3-thiazole-5-thione (36) undergoes a regioselective 1,3-dipolar cycloaddition reaction with a carbonyl ylide. The ylide is thermally generated by the electrocyclic ring opening of the epoxide (37) to give the spirocyclic adducts (38a and 38b) <97HCA1190>. 

Muthusamy and co-workers have demonstrated [82] the reactions of the bicyclic ylide 57, generated from the diazocarbonyl compoimd 56, with symmetrical and unsymmetrical dipolarophiles. Thus, exposure of the cyclohexanone-substituted a-diazocarbonyl compound 56 to DMAD in the presence of Rh2(OAc)4 as the catalyst has furnished the cycloadduct 58 (Scheme 16). This cycloaddition was diastereoselective and, in the case of unsymmetrical dipolarophiles such as methyl methacrylate and propargyl bromide, they were regioselective and afforded oxygen heterocycles 59 and 60, respectively. The same research group has reported the 1,3-dipolar cycloaddition of the bicyclic carbonyl yUde 57 with other dipolarophiles, namely fulvenes [83]. In these tandem cycUzation-cycloaddition reactions involving fulvenes, four stereocenters and two new C-C bonds are formed in a single step. Symmetrical dipolarophiles such as macrocycHc olefins were also used for diastereoselective 1,3-dipolar cycloaddition reaction with 56 [84]. 

Dipolar cycloaddition reactions constitute a powerful and convergent tool for the preparation of various heterocyclic compounds, which have been widely applied in the synthesis of numerous natural products, pharmaceuticals, and functional materials. The chemistry of 1,3-dipolar cycloaddtion reactions has been well documented in a number of reviews [3]. In this section the focus is on transition-metal-mediated 1,3-dipolar cycloaddition reactions with some important 1,3-dipoles, including azides, diazoalkanes, carbonyl ylides, and azomethine ylides, rather than a full review of the reactions of all types of 1,3-dipoles. 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

The last comprehensive survey of this area dates back to 1984, when the two-volume set edited by Padwa, 1,3-Dipolar Cycloaddition Chemistry, appeared. Since then, substantial gains in the synthetic aspects of this chemistry have dominated the area, including both methodology development and a body of creative and conceptually new applications of these [3+ 2]-cycloadditions in organic synthesis. The focus of this volume centers on the utility of this cycloaddition reaction in synthesis, and deals primarily with information that has appeared in the literature since 1984. Consequently, only a selected number of dipoles are reviewed, with a major emphasis on synthetic applications. Both carbonyl ylides and nitronates, important members of the 1,3-dipole family that were not reviewed previously, are now included. Discussion of the theoretical, mechanistic, and kinetic aspects of the dipolar-cycloaddition reaction have been kept to a minimum, but references to important new work in these areas are given throughout the 12 chapters. 

Substituted norbornane derivatives have been synthesized by the reaction of norbornenes with carbonyl ylides derived from a-diazoketones by a 1,3-dipolar cycloaddition route (Equation 97) <2002TL5981>. These reactions occur in high yields and with excellent o o-selectivity (Table 8). 

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 . 

Prompted by our earlier work dealing with the internal dipolar cycloaddition reaction of mesoionic oxazolium ylides of type 74, we subsequently studied the rhodium(II) catalyzed reactions of the related a-diazo ketoamide system 154 <97JOC2001 04OL3241 05JOC2206>. Attack of the amido oxygen at the rhodium carbenoid produces a push-pull carbonyl ylide dipole (i.e., 155) that is isomeric with the isomiinchnone class of mesoionic betaines. 

Examples of 1,3-dipoles include diazoalkanes, nitrones, carbonyl ylides and fulminic acid. Organic chemists typically describe 1,3-dipolar cycloaddition reactions [15] in terms of four out-of-plane 71 electrons from the dipole and two from the dipolarophile. Consequently, most of the interest in the electronic structure of 1,3-dipoles has been concentrated on the distribution of the four Jt electrons over the three heavy atom centres. Of course, a characteristic feature of this class of molecules is that it presents awkward problems for classical valence theories a conventional fashion of representing such systems invokes resonance between a number of zwitterionic and diradical structures [16-19]. Much has been written on the amount of diradical character, with widely differing estimates of the relative weights of the different bonding schemes. 

The third typical reaction of carbenes is combination with a nucleophile. Carbenes are electron-deficient species, so they combine with nucleophiles that have reactive lone pairs. Addition of a carbonyl O to a carbene gives a carbonyl ylide, a reactive compound useful for making furan rings by a 1,3-dipolar cycloaddition reaction (see Chapter 4). 

Herein, a comparison is presented of the chemical differences that exist among the 1,3-dipolar cycloaddition reactions of acychc or cyclic carbonyl ylides with the major classes of dipolarophiles. It is hoped that this work will provide a useful reference and stimulate further efforts in this sphere, which has further potential for varied synthetic applications towards heterocycles and natural products. 

Scheme 14). The regiochemical outcome of the 1,3-dipolar cycloaddition reactions of the cyclic five-membered ring carbonyl yUde 48 with a variety of acycUc and cycHc alkenes having activated or inactivated r-bonds can be ra-tionaUzed [78,79] on the basis of frontier molecular orbital considerations, with the HOMO and LUMO of the carbonyl ylides dominating the reactions with electron-deficient and electron-rich dipolarophiles, respectively (Scheme 14). 

Suga and co-workers have studied [ 148] the effect of several Lewis acids in cycloadditions. Yb(OTf)3 was found to be effective in promoting the 1,3-dipolar cycloaddition reactions of six-membered ring carbonyl ylides derived from 89 or 80 with imines. In the absence of Lewis acid, no cycloaddition reaction occurred (Scheme 57). 

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