Cyclization ketenes

Vinyl etheis cyclize with ketenes to cyclobutanones (239). 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

This method for the preparation of cyclobutanone via oxaspiropentane is an adaptation of that described by Salaiin and Conia. The previously known large-scale preparations of cyclobutanone consist of the reaction of the hazardous diazomethane with ketene, the oxidative degradation or the ozonization in presence of pjrridine of methylenecyclobutane prepared from pentaerythritol, or the recently reported dithiane method of Corey and Seebach, which has the disadvantage of producing an aqueous solution of the highly water-soluble cyclobutanone. A procedure involving the solvolytic cyclization of 3-butyn-l-yl trifluoro-methanesulfonate is described in Org. Syn., 54, 84 (1974). 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

The mechanism of this reaction has not been thoroughly explored. Some work has been done in analysis of potential intermediates for the reaction, although these intermediates were generated using flash vacuum pyrolysis (FVP). Materials in this experiment were trapped and IR spectrum suggested the formation of a ketene prior to cyclization. 

The synthesis of this ring system was achieved by the reaction of the ketene aminal 79 with 3-morpholino-l-ethyl-l,2,4-triazinium tetrafluoro-borate 78 to give 80 (89IZV494). Cyclization of 78 with the bifunctional nucleophile 81 gave the pyrrolo[3,2-e][l,2,4]triazinones 82 (88TL1431). This reaction represents the first example of orthocyclization onto the 1,2,4-triazine ring by the addition of dienophiles at C-5,6 (Scheme 20). 

The N,0- and N,S-heterocyclic fused ring products 47 were also synthesized under radical chain conditions (Reaction 53). Ketene acetals 46 readily underwent stereocontrolled aryl radical cyclizations on treatment with (TMSlsSiH under standard conditions to afford the central six-membered rings.The tertiary N,0- and N,S-radicals formed on aryl radical reaction at the ketene-N,X(X = O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from (TMSlsSiH was investigated and found to provide higher selectivities than BusSnH. 

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

A thermally 1,5 Tf-shift induced by heating 1-ethoxy alkynes 60 to about 150°C led to ketenes 61. Subsequent cyclizations to give lactams 62 were achieved by attaching a M-benzamido function at C-6 or C-7 of a linear alkyl chain. Azepanones 62 (n = 1) and Azecanones 62 (n = 2) were generated in 68% and 58% yield, respectively. The formation of larger rings (n = 5,9) failed under the conditions reported (Scheme 12) [20]. 

Additions of silylated ketene acetals to lactones such as valerolactone in the presence of triphenylmethyl perchlorate in combination with either allyltrimethylsilane 82, trimethylsilyl cyanide 18, or triethylsilane 84b, to afford substituted cyclic ethers in high yields have already been discussed in Section 4.8. Aldehydes or ketones such as cyclohexanone condense in a modified Sakurai-cyclization with the silylated homoallylic alcohol 640 in the presence of TMSOTf 20, via 641, to give unsaturated cyclic spiro ethers 642 and HMDSO 7, whereas the 0,0-diethyllactone acetal 643 gives, with 640, the spiroacetal 644 and ethoxytrimethylsilane 13b [176-181]... 

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]. 

In Entry 13, the dioxinone ring undergoes thermal decomposition to an acyl ketene that is trapped by the solvent methanol. The resulting (3-keto-y,8-enoate ester then undergoes stereoselective cyclization. The stereoselectivity is controlled by the preference for pseudoequatorial conformations of the C(6) and C(9) substituents. 

Tocopheryl)propionic acid (50) is one of the rare examples that the o-QM 3 is involved in a direct synthesis rather than as a nonintentionally used intermediate or byproduct. ZnCl2-catalyzed, inverse hetero-Diels-Alder reaction between ortho-qui-none methide 3 and an excess of <2-methyl-C,<9-bis-(trimethylsilyl)ketene acetal provided the acid in fair yields (Fig. 6.37).67 The o-QM 3 was prepared in situ by thermal degradation of 5a-bromo-a-tocopherol (46). The primary cyclization product, an ortho-ester derivative, was not isolated, but immediately hydrolyzed to methyl 3-(5-tocopheryl)-2-trimethylsilyl-propionate, subsequently desilylated, and finally hydrolyzed into 50. 

Compound 133 was synthesized by the one-pot intermolecular cyclization of ketene aminal 132 with alkyl isothiocyanate (Equation 15) <1995BML1541, 1997BML651, 2002BMC1275>. 

Despite the latent reactivity of ketene thioacetals,3-4 some members of this class such as the title compound have been little studied, perhaps because of preparative inaccessibility. The only previously reported route to 2-methylene-1,3-dlthiolane involves monoacetylation of 1,2-ethanedithiol, cyclization to 2-methyl-1,3-dithiolan-2-yl perchlorate, and exposure of this salt to diisopropylethylamine in acetonitrile 5... 

The cyclobutenone 70 is transformed to the r/4-vinylketene complex 72 with (t/5-indenyl)Co(PPh3)2 71. The vinylketene complex 72 undergoes cyclization with alkynes to produce the corresponding phenols 73. FeCl3 oxidation of the (2-phenylvinyl)ketene complex, however, leads to the naphthol 74. A catalytic synthesis of phenols via the vinylketene intermediates 72 is achieved by the use of Ni(COD)2 as a catalyst [36]. (Scheme 26)... 

Anodic oxidation reactions have been utilized to reverse the polarity of enol ethers and to initiate radical cation cyclizations. As shown below, the ketene acetal 97 is oxidized on a... 

As mentioned in CHEC-II(1996) <1996CHEC-II(8)16>, 3//-pyrrolizin-3-one 2 and many other substituted analogues were synthesized by FVP of Meldrum s acid derivatives 189 via the in. ( ////-generated pyrrol-2-ylmethylidene ketenes 190 which cyclize by an intramolecular A-acylation (Scheme 43) <1997J(P1)2195, 2000J(P1)3584>. 

Partially saturated derivatives can also be prepared through aryl radical cyclization of A-2-halobenzoyl cyclic ketene-iVA-acetals <2005TL3801>. In this event, treatment of ketene-acetal 418 with Bu3SnH afforded good yield of cyclized products 419 and 420, as a mixture of two diastereoisomers, but with a total regioselectivity (Scheme 108). 

Chiral trms-fi-lactams. The silyl ketene acetal (1), derived from (1S,2R)-N-methylephedrine, reacts in the presence of TiCl, with benzylideneaniline (2) to give as the major products anti- and syn-3 in the ratio >10 1. Cyclization of the mixture gives the trans-p-lactam (4) in 95% ee. 

P-LactamsSilyl ketene acetals condense with imines in the presence of this catalyst to afford only or mainly anh -p-amino esters, which can be cyclized to trans-3-lactams. 

The silyl ketene acetal 2, prepared from ethyl 3-hydroxybutanoate, undergoes a similar condensation with benzylideneaniline but with syn-selectivity. The product cyclizes to a cis-fl-lactam (4). 

X-radiation of o-nitrosobenzaldehyde also brings about intramolecular hydrogen transfer to yield the ketene 57. Cyclization within this affords 5866. 

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