Cyclization 3+2 -Cycloaddition reaction

Cyclizations proceeding by nucleophilic attack at noncarbonyl centers Free radical cyclizations Cycloaddition reactions Experimental Procedures... 

The tandem cyclization-cycloaddition reaction of 1-diazoacetyl-7,7-dimethylbicyclo[2.2.1]heptan-2-one (1) with dimethyl butynedioate catalyzed by rhodium(II) acetate dimer in benzene at 25 °C, afforded a formal [3 + 2] cycloadduct 2 in 85% yield with complete diastereofacial selectivity48. This reaction is interpreted to proceed via rhodium carbenoids and subsequent transannular cyclization of the electrophilic carbon onto the adjacent oxo group to generate a cyclic carbonyl ylide. followed by 1,3-dipolar cycloaddition. Similar reactions are observed with other dipolar-ophiles, such as propargylic esters and A -phenylmaleimide. Studies dealing with the geometric requirements of dipole formation were undertaken. 

Adducts (e.g., 5) from Tandem Cyclization-Cycloaddition Reaction of Diazo Ketone 4 with Dipolarophilcs General Procedure85 ... 

A tandem cyclization-cycloaddition reaction was developed as a method for synthesizing polycyclic ring systems which involved a rhodium(II) acetate-induced diazoketone cyclization onto a neighboring carbonyl group to generate an ylide followed by 1,3-dipolar cycloaddition. Thus (208) has been transformed into the 8-substituted pyrrolizidone (209) <89JA645l). 

Padwa A, Price AT (1995) Tandem cyclization-cycloaddition reaction of rhodium carbenoids as an approach to the aspidosperma alkaloids. J Org Chem 60 6258-6259 59. Padwa A, Price AT (1998) Synthesis of the pentacyclic skeleton of the aspidosperma alkaloids using rhodium carbenoids as reactive intermediates. J Org Chem 63 556-565 Mejia-Oneto JM, Padwa A (2004) Intramolecular [3+2]-cycloaddition reaction of push-pull dipoles across heteroaromatic p-systems. Org Lett 6 3241-3244 61. Padwa A, Lynch SM et al (2005) Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems. J Org Chem 70 2206—2218... 

An efficient protocol for the synthesis of syn-facially bridged norbornane frameworks has been developed via the tandem cyclization-cycloaddition reactions of the carbonyl ylide 57 with norbornene derivatives. The reaction of the diazo ketone 56 with the dipolarophile 62 in the presence of Rh2(OAc)4 furnished [85] the 5y -facially bridged oxa-norbornane framework 63 in high yield (Scheme 17). 

Seven-membered ring carbonyl ylides derived from phthalimides can also participate in these tandem cyclization-cycloaddition reactions, the Rh2(OAc)4-catalyzed reaction of l-diazo-4-phthalimidobutanone (226) pro-... 

Scheme 14.53 Chiu s synthesis of (-)-indicol (340) by a rhodium-catalyzed domino carbene cyclization/cycloaddition reaction.

A number of examples such as 1,3-dioxanes, macrolactones, °° ring-containing biaryls, ° spirooxindoles, alkaloid-like compounds, and polycyclic compounds from the Schreiber group illustrate this approach to natural product-like libraries (see Chapter 11). An early example converted shikimic acid into intermediate tetracyclic y-butyrolactones, which were then functionalized around the core structure (see Chapter 11, Subsection 11.10.2). y-Butyrolactones, found in about 10% of all natural products and which exhibit a broad range of biological activities, are a key element in a number of recent natural product-like compounds. A more recent example, inspired by the rich skeletal diversity of indole alkaloids, utilized the rhodium(II)-catalyzed consecutive cyclization-cycloaddition reactions developed by Padwa and coworkers (Scheme 1.4). A stereocontrolled tandem reaction utilizing the versatile scaffold allowed for multiple modes of intramolecular reactions. 

We then investigated conditions for the cycloaddition of 8 / with 6 /. The effects of solvents and catalysts were studied. Using 1,3,5-trimethoxybenzene as an internal standard, the yield of the reaction and exo. endo ratio could be determined directly by careful integration of the H NMR of the crude reaction mixture. For solvent studies, Rh20ct4 was used as the catalyst, and 1.5 equivalents of enone were used in the reaction. The results are listed in Table 9.3. The effect of solvents on the Rh (Il)-mediated cyclization/cycloaddition reaction is quite subtle. Ethereal solvents generally... 

Xie YX, Yan Z Y, Qian B, Deng WY, Wang DZ, Wu LY, Liu XY, Liang YM (2009) A novel iodine-mediated tandem cyclization-cycloaddition reaction leading to polyoxacyclic ring systems. Chem Commun 2009 5451-5453... 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Thermal and photochemical cycloaddition reactions always take place with opposite stereochemistry. As with electrocyclic reactions, we can categorize cycloadditions according to the total number of electron pairs (double bonds) involved in the rearrangement. Thus, a thermal Diels-Alder [4 + 2] reaction between a diene and a dienophile involves an odd number (three) of electron pairs and takes place by a suprafacial pathway. A thermal [2 + 2] reaction between two alkenes involves an even number (two) of electron pairs and must take place by an antarafacial pathway. For photochemical cyclizations, these selectivities are reversed. The general rules are given in Table 30.2. 

Padwa A., Fryxell G. E. Cyclization and Cycloaddition Reactions of Cyclopropenes Strain Org. Chem. 1991 1 117-166... 

As applied to cycloaddition reactions the rule is that reactions are allowed only when all overlaps between the HOMO of one reactant and the LUMO of the other are such that a positive lobe overlaps only with another positive lobe and a negative lobe only with another negative lobe. We may recall that monoalkenes have two n molecular orbitals (p. 9) and that conjugated dienes have four (p. 36), as shown in Figure 15.1. A concerted cyclization of two monoalkenes (a 2 -f- 2 reaction) is not allowed because it would require that a positive lobe overlap with a negative lobe (Fig. 15.2). On the other hand, the Diels-Alder reaction (a 2 -f 4 reaction) is allowed, whether considered from either direction (Fig. 15.3). 

Uemura M (2004) (Arene)Cr(Co)3 Complexes Cyclization,Cycloaddition and Cross Coupling Reactions. 7 129-156 Ujaque G, see Drudis-Sole G (2005) 12 79-107... 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

The intramolecular formal [3+3] cycloaddition reaction of l- [l-phenyl-2-(4-oxobut-2-enyloxy)ethyl]amino cyclo-hexen-3-one at 150°C in the presence of piperidinium acetate afforded /ra 3--l,4a-77-l-phenyl-l,2,4,4a,7,8,9,10-octahydro[l,4]oxazino[4,3- ]quinolin-7-one <2002JA10435>. At 85°C, the 6-(l-piperidnyl)-l,2,4,4a,5,6,7,8,9,10-dec-ahydro derivative formed, which could be converted into the l,2,4,4a,7,8,9,10-octahydro derivative by heating at 150 °C. Cyclization of iV-[(2-butyl-2-oxoethoxy)acetyl]-3,4-dimethoxyphenylethylamine on the action of TFA gave llb-butyl-1,3,4,6,7,1 lb-hexahydro[l,4]oxazino[3,4- ]isoquinolin-4-one <1997JOC2080>. 

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