Cyclohexanone dialkylation

The above is an example of the Guareschi reaction. It is applicable to most dialkyl ketones and to alicyclic ketones (e.g., cyclohexanone, cyc/opentanone, etc.). The condensation product (I) is probably formed by a simple Knoe-venagel reaction of the ketone and ethyl cyanoacetate to yield ethyl a-cyano-pp dimethylacrylate (CH3)2C=C(CN)COOCjHj, followed by a Michael ad tion of a second molecule of ethyl cyanoacetate finally, the carbethoxyl groups are converted to the cyclic imide structure by the action of ammonia. 

Arbeitet man mit symmetrischem 1,2-Dialkyl-hydrazin, also ohne den Phenylrest, so kann dieses Verfahren zur Synthese von Pyrrolen Verwendung fxnden 6i,62)- Die rein thermische Reaktion ist auch hier kein brauchbares Verfahren, unter scbwacher Saurekatalyse bildet sich jedoch aus Cyclohexanon 118 und bei sukzessiver Einwirkung von Dime-don und Cyclohexanon 119. 

Using (—)-(.S )-a-(methoxymethyl)bcnzeneethanamine as chiral auxiliary, metalation of a-alkylated cyclohexanone imines can be performed by refluxing THF solutions with LDA for 2 hours. In general, metalation occurs at the less substituted carbon resulting in oc.oc-dialkylated products8 after alkylation at — 78 °C. 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

Michael addition.1 This ketene silyl acetal undergoes Michael addition to a,fl-enones in acetonitrile in the absence of a Lewis acid to afford the corresponding O-silylated Michael adduct in high yield. These O-silyl enolates undergo site-specific electrophilic substitution. This sequence was used for vicinal dialkylation of cyclohexanone (equation I) and of cyclopentanone. It is particularly useful for synthesis of methyl jasmonate and related compounds from cyclopentenone. 

A series of [3-carbonyl sulfides was studied as substrates for CPO-catalyzed oxygenation (Scheme 2.16) [238]. The corresponding dialkyl sulfoxides formed quantitatively if R2 is methyl or ethyl, but the yields drop dramatically for larger substituents. The steric control was present also in cyclic derivatives where the cyclohexanone residue results in about a 50% reduction in yield with respect to the smaller cyclopentanone. Surprisingly, the y-butyrolactone produces the sulfoxide in quantitative amounts [239]. A similar result was obtained with benzo[fo]thiophenes as substrates [240]. 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

C-Alkylation affords monoalkylated products as a result of the lower reactivity of the monoalkylated enamines. Enamine salts obtained by alkylation can afford new enamines capable of further alkylation only by the loss of a proton. In some cases, dialkylation can be achieved by the addition of the more basic ethyldicyclohexylamine. Monoalkylation of the pyrrolidine enamine of cyclohexanone is due to a considerable energy difference between the transition states caused... 

Bobbitt et al.113 reported that when benzylaminoacetaldehyde dialkyl acetals (18) are heated under reflux with concentrated hydrochloric acid and ethanol, in the presence of benzaldehyde, good yields of the 4-benzylisoquinoline derivatives (85), via the 1,2-dihydroisoquinoline (82), can be isolated. A mechanism for this reaction114 is summarized in Scheme VI. With cyclohexanone enamine and aldehydes, the intermediate has been formulated115 as 86. It was originally reported114 that an intermediate of the... 

The presence of water may lead to the formation of cyclohexanone or cyclohexanol by the hydrolysis of the enamine or imine intermediate.204,205 The hydrolysis takes place especially readily in the hydrogenation of A,/V-dialkyl anilines (eq. 11.57). 

Returning to the unsubstituted cyclohexanone enamine, the use of ethanol as solvent instead of benzene favours 2,6-dialkylation. In addition to the octalone dienamines this has resulted in the isolation of the tricyclic dione 149293 (Scheme 135). The same ring... 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

Medium-sized cyclic ketones have been enantioselec-tively alkylated via their chiral lithioenamines to yield 2-alkylcycloalkanones in 80-100% ee. This procedure has also furnished a,a -dialkyl cyclohexanones in good enantiomeric excess (eq 2). Based on this protocol, regiospecific deutera-tion of 3-methylcyclohexanones has been achieved with good enantioselectivity. ... 

In an alternative procedure (I) is dialkylated to give the salt (3) this can be hydrolyzed with 10% NaOH solution to give cyclohexanone in 81 % yield. Using this procedure. 

Yamamoto and Saito reported that the kinetically controlled generation of the more substituted enolate of unsyimnetrical dialkyl ketones can be realized by the combined use of ATPH and LDA [175]. Precomplexation of ATPH with 2-methyl-cyclohexanone (175) at -78 °C in toluene was followed by treatment with LDA in THF, and the mixture was stirred for 1 h. Subsequent treatment with methyl trifluoro-methanesulfonate (MeOTf) furnished 2,2-dimethylcyclohexanone (177) and 2,6-dimethylcyclohexanone (176) in the ratio 32 1 (53 % isolated yield). Use of ter/-butyl-dimethylsilyl triflate (TBSOTf) in place of alkyl triflates in this alkylation system produced siloxybutylated product 178 as a result of THF ring-opening alkylation occurred similarly at the more hindered a-carbon of the unsymmetrical ketone 175 (Sch. 136) [176]. 

The above conditions allow the synthesis of a large variety of a,a-dialkyl substituted ketones including spiro derivatives and cyclopentanones, cyclohexanones, cycloheptanones and cyclododecanones bearing two alkyl groups at die a-posidon (Scheme 162, e Scheme 165, c Scheme 166, e Scheme 186, a and b Scheme 187 Scheme 188, a Scheme 189, a and The reactions are less selective when the dichlorocarbene is generated from bromodichloromethane and lead to gem-dichlorocyclopropanes if the dichlorocarbene is produced from chloroform and potassium r-butoxide (Scheme 162, f Scheme 188, b Scheme 189, c). ... 

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

On the other hand, recent work16) shows that it is also possible to alkylate imines in THF in the presence of the complex base NaNH2-Et(OCH2CH2)20Na. Thus cyclohexylimines of butyraldehyde and cyclohexanone are monobenzylated by Ph-CH2 -Cl with 40% and 80% yields respectively. Dialkylation is never more than 5%. 

Whitesell and Felman therefore concluded that an amine with a C2 axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The en-antioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from ( + )-/mnj-2,5-dimethylpyrrolidine. This was assumed to have the S, S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed (4-7%) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of 4-substituted cyclohexanone enamines to give mainly the less stable trans disubstituted cyclohexanone s . 

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