Ketenes intramolecular cycloaddition

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). 

Scheme 6.8 gives some examples of ketene-alkene cycloadditions. In Entry 1, dimethylketene was generated by pyrolysis of the dimer, 2,2,4,4-tetramethylcyclobutane-l,3-dione and passed into a solution of the alkene maintained at 70° C. Entries 2 and 3 involve generation of chloromethylketene by dehydrohalo-genation of a-chloropropanoyl chloride. Entry 4 involves formation of dichloroketene. Entry 5 is an intramolecular addition, with the ketene being generated from a 2-pyridyl ester. Entries 6, 7, and 8 are other examples of intramolecular ketene additions. 

Intramolecular cycloaddition of chiral ketene 3 has been successfully employed in the synthesis of both ( + )- and ( —)-grandisol, the principal pheromone of the boll weevil.14 Although a mixture of diastereomers 4 A and 4B is obtained, the products are optically pure. 

Ketene reactivity in intramolecular cycloadditions parallel those in intermolecular reactions in which chloro-, vinyl-, aryl- and alkoxyketenes are more reactive than the alkylketenes. In most instances the ketene is generated by amine dehydrohalogenation of an acid chloride. There are, however, a few examples of ketenes prepared along less conventional routes as by the examples for the formation of 11.150 12,151 and 13.151... 

Intramolecular [2n + 27r] cycloadditions leading to cyclobutanes formally belong to valence isomerizations. Alkene/alkcne, ketene/alkene, and allene/alkene cycloadditions have received detailed attention. These rearrangements provide powerful methods for the synthetic arsenal. An example is the facile synthesis of bieyelo[3.2.0]heptenones 3 by intramolecular ketene/alkene cycloaddition after electrocyclic ring opening of cyclobutenoncs l.89... 

Synthesis of the dibenzofuran (27) by irradiation of grisa-3, 5 -diene-2, 3 -dione (28) is believed to involve electrocyclic ring opening followed by intramolecular cycloaddition to the ketene and elimination of carbon dioxide, as shown in Scheme 2.24 Analogous photocyclizations are responsible for the photochromism exhibited by heterocyclic fulgides such as ( )-a-3-furyl-ethy idene(isopropylidene)succinic anhydride (29), which on irradiation... 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

The reaction proceeds through a vinylketene (54) formed via a vinylcarbene (53) the product of ring-opening of the cyclopropene ring. Then, the ketene undergoes intramolecular cycloaddition in benzene or is trapped by methanol (equation 35) °. 

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

The intramolecular cycloaddition of ketenes with alkenes is a versatile synthetic procedure for the preparation of bicyclo[3.2.0]heptan-6-ones and bicyclo[3.3.1]heptan-6-ones19a-b. Three-atom tethers offer the best compromise between product strain, which is prohibitive with two-atom tethers, and entropy of activation, which decreases the rate of reaction with longer tethers. Cycloadditions with four-atom tethers arc quite rarc19a,b. As in intcrmolccular cycloadditions, syn addition to the alkene normally occurs. 

Mixtures of diastereomers are obtained from intramolecular cycloadditions leading to bicy-clo[n.2.0]alkanones of ketenes with stereogenic centers on the tether. The diastereoselectivity is usually modest and the reasons for the selectivity observed are not always obvious. 

Malonyl chloride enolizes and cyclizes to form a pyranone (325) which combines with dialkyl-cyanamides to yield pyrano[4,3- ][l,3]oxazinediones (328), as well as pyranoazetediones (329). Presumably, the first step is the formation of adducts (326), which undergo rearrangement to the ureas (327) and elimination of hydrogen chloride to yield ketenes. Alternate intramolecular cycloadditions of the ketenes afford the final products (Scheme 93) <85CB4707>. 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

Optically active 3-lactones are readih p using 72 as the chirality inducer. - - The p acids. The [2 -f 2]cycloaddition of ketenes ai nine leads to numerous c y-2,3-disubstituted f Reports on the advances of asymmetric 1 of diazoalkanes to A-(2-alkenoyl)oxazolidin-. 73, showing cooperative chiral control by the ral ligand.An intramolecular cycloaddition a chiral cyclic A,N -dimethylaminal unit ad>i 74) proves very successful in the asymmetric nitrone lacks stereoselectivity, - ... 

The masked 1,3-dipole, thiatriazole (135), undergoes intramolecular cycloaddition with subsequent elimination of molecular nitrogen, smoothly in ethanol at 75 C to give (136). These reactions were studied in detail with iso thiocyanates, isocyanates, ketenes, and electrophilic nitriles <92T7505>. 

The intramolecular ketene-alkene cycloaddition has also been used to prepare highly substituted phenols. As originally formulated, a cyclobutenone such as 342 was converted to a phenol derivative (346). When 342 was heated in benzene, ketene 343 was formed. When done in the presence of an alkyne,281 an in situ [2+21-cycloaddition led to a new cyclobutenone (344) but under the reaction conditions, a four-electron electro-cyclic cleavage reaction occurred to give 345. This compound also reacted, via a six-electron electrocyclic... 

Scheme 50). An alternate approach to the oxindole C3 to C7 bicyclic core found in members of welwitindolinone family has been reported by the Shea and coworkers who set the C3 linkage via a Znl2 promoted coupling of silyl ketene aminal 204 with functionalized furan 205 (Scheme 51) [120]. An intramolecular cycloaddition between C3 tethered furan of 206 and C7 pendant a,p-imsaturated ester closed the bridged oxindole scaffold of 207 in 41% yield. 

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. ... 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

Neooctams, such as the unsubstituted parent compound (191), are easily obtained in cycloadditions. Isocyanates [125,126], sulphonyl isocyanates (43) [29,127] and especially chlorosulphonyl isocyanate (189) [128] react with alkenes to form variously-substituted j3-lactams [129—135]. Synthesis of compound (191) is an example of this reaction which has been discussed in detail [52]. The same compound (192) can be obtained in the photolytic rearrangement of the pyrazolone (194) [136]. Compound (196) is neooctam-5,7-diene, obtained from the azocine (195) and hydrogen bromide [137]. Lactam (196)is a partly saturated form of (199). The latter is an unstable neooctam derivative, formed in an intramolecular ketene-imine cycloaddition reaction (see (198))... 

Certain cycloaddition/cyclization processes produce substrates for the quasi-Favorskii rearrangement with good yield and selectivity. For example, the intramolecular cycloaddition of ketene 45, available by dehydrohalogenation of the corresponding acid halide 44, afforded 46 in moderate yield (Scheme 7.131. This conpound reacted smoothly with lithium hydroxide under mild conditions to form the carboxylic acid 47. ... 

It may be noted that when the terminal carbon of the olefin is more substituted, the intramolecular cycloaddition of ketenes leads to the formation of bicycle[n. 1.1]alkanones as shown below ... 

The ketene 58, generated by a Wolff rearrangement of 57, undergoes intramolecular cycloaddition across the ester C=0 group to give 59 (Scheme 20) (1992JCS(P1)2837). 

Georg and coworkers reported a C=C bond cycloaddition with a ketene to provide six-membered enaminones, under mild conditions (Scheme 92) (2010JA15512). From this intramolecular cycloaddition of a ketene created from diazoketone 289, employing a silver-catalyzed Wolff rearrangement, a six-membered enaminones such as 290 was obtained. 

They react with alkenes to give cyclobutanone derivatives, and their intramolecular cycloadditions are well known. Ketenes have been used in the synthesis of y-lactams, drug intermediates and other area as chemical intermediates. 

---