Cycloaddition reactions 2+2 of ketenes

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

Cycloaddition reactions of ketenes with alkenes have long been known to give cyclobutanones [123] and to proceed with retention of the configurations [124], The reactions were classified into the symmetry-allowed cycloaddition reactions... 

Scheme 25 Pseudoexcitation in the [2+2] cycloaddition reactions of ketenes with alkenes...

Diels-Alder reactions [31] and 1,3-dipolar cycloadditions [32, 33] have been performed by use of this methodology. For example, Diaz-Ortiz described the hetero-Diels-Alder and 1,3-dipolar cycloaddition reactions of ketene acetals. The reactions were improved and products were isolated directly from the crude reaction mixture without polymerization of the ketene acetals [34],... 

The cycloaddition reactions of ketenes with cyclopentadiene have been known to give formal [2 + 2] cycloadduct (35) instead of [4 + 2] Diels Alder products (34) (Scheme 8). A combined computational and experimental study suggested that the reaction initially gives [4 + 2] cycloadduct, which subsequently rearranges to 35 via [3,3] sigmatropy.91,92 The MP2/6-31G //HF/3-21G calculations... 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

The (2 + 2) cycloaddition reactions of ketenes with alkenes are synthetically useful routes to cyclobutanones. Ketenes are particularly useful due to the low steric hindrance at the carbonyl carbon. An example is the reaction of dichloro-ketene with cyclopentadiene which, after reductive dechlorination of the product, gives bicyclo[3.2.0]hept-2-en-6-one (Expt 7.25). 

Lactams are also obtained in the [2-1-2] cycloaddition reaction of ketenes with carbodiimides (see Section 2.4.2.1). 

Mixed substituted orthoesters, e.g. (383 equation 180), can be obtained by addition of alcohols to ketene 0,0-acetals. With the aid of phosphoranes containing a ketene O,(7-acetal structure, various orthoesters, e.g. (384) and (385) (Scheme 70) were prepared. " Cyclic orthoesters (386)-(390) (Scheme 71) are formed in cycloaddition reactions of ketene 0,0-acetals with aldehydes, ketones, 7.848 gj.yj cyanides, oxiranes, a-keto esters, o-diketones or ketones (with irradiation), a,3-unsaturated aldehydes and ketones (under pressure or catalyzed by ZnCh), diazoaceto-phenone, 7 diazoacetone and azodicarboxylate. ... 

Snider, B. B. Intramolecular cycloaddition reactions of ketenes and keteniminium salts with alkenes. Chem. Rev. 1988, 88, 793-811. 

Cossio, F. P., Lecea, B., Cuevas, C., Mielgo, A., Palomo, C. A novel entry for the asymmetric Staudinger reaction experimental and computational studies on the formation of P-lactams through [2+2] cycloaddition reaction of ketenes to imines. An. Quim. 1993, 89, 119-122. 

Parvulescu, L. Cycloaddition reactions of ketenes with bicyclic systems. Roumanian Chem. Quart. Rev. 1995, 3,187-200. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

Photochemical [2+2] cycloaddition reactions and [2+2] cycloaddition reactions of ketenes have been widely used for the preparation of cyclobutane derivatives. The thermal [2+2] cycloaddition reaction is known to proceed between highly electrophilic and nucleophilic alkenes alkenes having cyano, fluoro, and trif-luoromethyl groups react with electron-rich alkenes such as alkenyl ethers and sulfides [8]. As for the catalyst-mediated [2+2] cycloaddition reactions, Lewis acids are known to promote [2+2] cycloadditions [9,10,11,12,13,14,15,16,17,... 

Cinchona alkaloids are the effective asymmetric catalysts in the [2+2] cycloaddition reaction of ketenes and aldehydes [47]. That is, the reaction between ketenes and chloral proceeds with a catalytic amount (2.5 mol %) of quinidine in toluene at -50 °C to provide the P-propionolactone (-)-18 in quantitative yield with 98% ee (Scheme 17). 

The (2 + 2)-cycloaddition reactions of ketenes with heterocycles via an endocyclic imino group have contributed substantially to the synthesis of penicillin (92a) and cephalosporin C (93a) antibiotics and structurally related heterobicyclic /Mactams.7 11 Reactions with relatively stable ketenes, e.g., diphenylketene, have been reported as well as reactions of heterocycles with mixtures of acid chlorides and tertiary amines. 

This means that reaction III is more exothermic than reaction IV, and the product of reaction III is thermodynamically more stable than the product of reaction IV. Hence, the expected product is the one formed in reaction III. This is in fact the actual product obtained from the 1,2-cycloaddition reaction of ketene with cyclo-pentadiene. 

The Bose research group has developed a large variety of [2+2] cycloaddition reactions of ketenes with imines to form yS-lactams [16, 112, 113]. In 1991, Bose et al. described the synthesis of a-vinyl yS-lactams by [2-p2] cydoaddition of a,p-unsaturated acyl chlorides with a SchifF base in chlorobenzene. Reaction times were reduced from several hours with conventional methods to 5 min under the action of microwaves [112], and yields of the desired adducts were improved from very low to approximately 70% when compared with classical methods. 

Cycloaddition reactions of ketenes with dienes are rapid and normally lead to the cyclobutanone product, rather than the Diels-Alder adduct. There is evidence that the cyclobutanone forms by a two-step process, involving an initial [4-1-2] cycloaddition of the diene and the ketene carbonyl group, followed by a [3,3]-Claisen rearrangement. 

DicWoroketene is particularly reactive, and reductive dechlorination of the product with zinc and acetic acid allows access to the cyclobutanone from formal addition of ketene itself. Thus, cycloaddition of dichloroketene with cyclopentadiene, followed by dechlorination and Baeyer-Villiger oxidation gave the lactone 173, a usehil precursor to various oxygenated cyclopentane products (3.117). Intramolecular cycloaddition reactions of ketenes can allow the formation of bicyclic and polycyclic products using otherwise unstable ketene intermediates. ... 

Enantioselective cycloaddition reactions of ketenes catalyzed by N-het-erocyclic carbenes 13SL1614. 

New types of combined pericycHc reactions 13UK228. Organocatalytic asymmetric cycloaddition reaction of ketenes 12CJ057. Pericyclic [4+2] and [3+2] cycloaddition reactions of nitroarenes in heterocyclic synthesis 13KGS102. 

Ketenes are compounds with adjoining carbon-carbon and carbon-o>grgen double bonds. Possessing highly reactive carbonyl and alkenyl moieties, ketenes are remarkable for their many possible transformations, particularly for their use in cycloaddition reactions. NHC-catalysed enantioselective cycloaddition reactions of ketenes have been intensively explored over the past decade. 

In 2008, Ye and coworkers developed the NHC-catalysed [2 + 2] cycloaddition reaction of ketenes with 2-oxoaldehydes, resulting in formation of the corresponding p-lactones 163 in good to excellent yield and with high diastereo- and enantioselectivity (Scheme 20.68). 

The group subsequently found that trifloromethyl ketones and isatins were suitable electrophiles for the NHC-catalysed [2 + 2] cycloaddition reaction of ketenes, ° giving the eorresponding trifluoromethyl-substituted p-lactones 165 and spiroeyelie oxindole-p-laetones 167, respectively, in good yields with high enantioselectivities (Scheme 20.69). 

The [4 + 2] cycloaddition reactions of ketenes are efficient approaches to six-membered heterocycles. In 2008, Ye and coworkers reported a NHC-catalysed [4 + 2] cycloaddition reaction of disubstituted ketenes with enones to give the corresponding -lactones 183 in good yield and with good diastereoselectivity and high enantioselectivity. The frans-isomers were... 

Unlike the [2 + 2]-cycloaddition reaction observed with azodicarbo ylates and ketenes, the Ye group reported the NHC-catalysed [4 -P 2] cycloaddition reaction of ketenes with N-benzoyldiazenes. Opposite enantioselectivities were observed for the reactions catalysed by NHC precursors Cll and C12. The bullg mesityl substituent and the free-hydroxyl group in catalyst may play a role in switching the enantioselectivity (Scheme 20.82). 

Recently, the group developed NHC-catalysed [4 + 2] cycloaddition reaction of ketenes to 1-azadienes. A series of chiral dihydropyridinones 195 were obtained in high 5rield and with good diastereo- and enantioselectivity (Scheme 20.83). 

There is an alternative description of the [2 + 2] cycloaddition reactions of ketenes. This formulation is [ItTs + (277 + The basis set orbital array is... 

Catalytic enantioselective cycloaddition reactions of ketenes have been intensively explored over the past several decades. Various chiral catalysts have been developed for these cycloadditions, such as cinchona alkaloids, N-heterocyclic carbene (NHC) catalysis (2013SL1614), planar-chiral 4-(JV,JV-dimethylamino)pyridine (DMAP)-derived catalysts, and Lewis acid-based catalysts (2009T6771, 2004ACR542). 

In 2011, Ye et al. reported that NHCs can be used as effective catalysts for the conventional [4 + 2] cycloaddition reactions of ketenes. NHC 46, created in situ from its common precursor 46 in the presence of CS2CO3, catalyzed the reaction of a, d-unsaturated acyl chlorides 43 and activated trifluoromethyl ketones 44, promoted by Et3N to afford the corresponding optically active trifluoromethyl substituted 5-lactones 45 (Scheme 16) (2011MI1943). Activated ketones as isatin and its derivatives have been fruitfully employed as electrophiles in this reaction. This reaction is... 

The scope of this cycloaddition is weU illustrated by the synthesis of 94, 96, and 98 via a [4 + 2] cycloaddition reaction of ketene with unsaturated ketones 93, 95, and 97, respectively (Schemes 30—32) (1979CB1791, 1978JHC181). 

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