Carbenes cyclic ketones

A sequence of reactions for conversion of acyclic and cyclic ketones into a,(3-unsaturated ketones with insertion of a =CHCH3 unit has been developed. The method uses l-lithio-l,l-dichloroethane as a key carbenoid reagent. The overall sequence involves three steps, one of them before and one after the carbenoid reaction. By analysis of the bonding changes and application of your knowledge of carbene reactions, devise a reaction sequence that would accomplish the transformation. 

The signature application for the G-H insertion in synthesis is probably the total synthesis of (—)-tetrodotoxin 126 by Du Bois and Hinman.233 Two stereospecific G-H activation steps, rhodium-catalyzed carbene G-H insertion and carbamate-based nitrene C-H insertion, have been used to install the two tetrasubstituted centers C6 and C8a (Scheme 12). Diazoketone 122 was treated with 1.5mol% Rh2(HNCOCPh3)4, and cyclic ketone 123 was selectively formed in high yield without purification. The reaction of carbamate 124 with 10mol% Rh2(HNCOCF3)4, PhI(OAc)4, and MgO in C6H6 solvent furnished the insertion product 125 in 77% yield. 

In reactions which have some analogy with the interaction of dichloro-carbene/trichloromethyl anions with ketones, 2-dichloromethyloxazolines yield chloro-oxiranes and a-chlorocarbonyl compounds (Scheme 7.18). The formation of the oxiranes is favoured with aldehydes and lower homologue ketones, whereas cyclic ketones and aryl ketones are converted preferentially into the a-chloro carbonyl derivatives [18]. 

Enol ether or silyl enol ether as an alkene in RCM can be used by the second-generation mthenium carbene complex Ig. It affords the cyclic enol ether or silyl enol ether, which gives a cyclic ketone [Eqs. (6.17) and (6.18)] °... 

At the opposite end of the philicity spectrum, nucleophilic carbenes have proven useful in synthesis. Warkentin" pioneered the thermolysis of oxadiazolines as precursors for (CH30)2C and related dioxacarbenes (Scheme 7.3). Dimethoxycarbene generated from an oxadiazoline undergoes a variety of intermolecular reactions." One example is the ring enlargement of strained cyclic ketones, for example, cyclo-butanone. In this reaction, the nucleophilic carbene initiates the ring expansion by... 

Using this rearrangement, ( )-muscone has been synthesized in 76% yield from a bromo alcohol which was formed by reaction of lithium dibromomethane with the corresponding cyclic ketone (equation 191)"2. Other ring expansions of this type have been reported to occur in reasonable yields and there are some indications that the reaction may go via a carbene intermediate994-1002. 

Carbene transfer from the silver(I) complex is not only possible to ruthenium(II) to form a catalyst suitable for asymmetric olefin metathesis, but also to copper(I) [17]. This provides a catalyst suitable for copper(I) catalysed conjugate addition of alkyl- and arylzinc reagents to P-substituted cyclic enones. The products, chiral cyclic ketones, are obtained in 88-95% isolated yield and 67-83% ee. 

Ring expansion to a carbene is one of the many reactions of interest which small ring cyclic ketones undergo. The kinetics of the photo-ring expansion of ketones to carbenes has been studied and the formation of the carbene in alcohol has been shown to be irreversible. Thus the irradiation of the ketone (14)... 

The Fritsch-Buttenberg-Wiechell rearrangement provides a method to expand a cyclic ketone to a cyclic acetylene with an additional carbon atom in the ring [34]. The ketone is first converted to a vinyl bromide or a vinylidene dibromide, from which the corresponding vinylidene carbene is produced with butyllithium. The vinylidene carbene then rearranges to a cyclic alkyne (Scheme 8-10). 

In 2013, the first successful generation of ds-homoenolate equivalents from ds-enals under the catalysis of N-heterocyclic carbene D4 was developed by the Chi group. The ds-homoenolate intermediates I undergo effective reaction with a,p-unsaturated imines to afford chiral cyclic ketones 62. Compared to the trans-enals, ds-enals show different stereoselectivities and new reactivity patterns (Scheme 20.29). 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Cyclic ketones 11 and 13 on photoirradiation in hydroxylic solvents give acetals 12 and 14, respectively, by a-cleavage followed by formation of carbene and subsequent reaction with solvent [11]. 

Cycloaddition of methyl chloromethylene carbene to silyl enol ethers is the first step in a short sequence to ring-expand cyclic ketones to a-methylcyclo-alkenones [equation (20)]. Thermal elimination of chlorotrimethylsilane com-... 

Paramagnetic species possessing two unpaired electrons (biradicals, carbenes, and their analogues) have been intensively studied using CIDNP techniques in high and low magnetic fields. The involvement of biradicals in organic and biochemical reactions is postulated in a number of cases, but the physical methods (EPR, laser spectroscopy) have allowed the detection of their formation predominantly in the photolysis of cyclic ketones. These species have also served as models for detailed studies of CIDNP peculiarities for biradicals, as well as the distinction of these effects from the case of free radicals. 

From the reactions presented in this section one can conclude that cyclic acetal formation via addition to a carbene intermediate is a general reaction for type I cleavage of cyclobutanones, tricyclic compounds, and certain bridged bicyclics as minor products. No acetal has been isolated from photolyses of cyclopentanones or cyclohexanones except for the special case of an a-sila ketone previously discussed. 

Os(II) complexes of tosylmethylisocyanide react with aldehydes and ketones in the presence of sodium methoxide, producing cyclic carbene complexes (66). Compound 32 undergoes a rapid reaction with benzal-dehyde and NaOMe, yielding the oxazol-2-ylidene complex 33 and eliminating p-toluene sulfinic acid (66) ... 

Acyclic and cyclic allylic ethers and acetals react normally with dihalocarbenes at the C=C bond [e.g. 77, 85, 108,114,121,122], Carbene insertion into the C=C bond of allylic ketones, which can be complicated by competitive reaction by the carbonyl group, can also be effected via the initial formation of the acetal and has been used in the synthesis of cyclonona-3,4- and -4,5-dienones from cyclooctenones [125],... 

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