Cyclohexanone reaction with benzaldehyde

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

The addition of nitromethane to cyclohexanone was completed in 1 h at 0 °C, affording product 32 in 82% yield as expected the reaction with benzaldehyde afforded the corresponding product 33 in 95% yield in only 5 min at the same temperature. However, the reaction was not generally applicable as other aliphatic ketones and acetophenone did not react. 

Benzaldehyde and isobutyraldehyde have been used as co-reductants in aerobic BV oxidation of cyclohexanone, catalysed by iron(III) porphyrins. The dramatic difference in the yield of e-caprolactone (96% for benzaldehyde and 11% for isobutyraldehyde) has been investigated kinetically, leading to elucidation of a mechanistic difference. The reaction with benzaldehyde involves a high-valent iron porphyrin, whereas the isobutyraldehyde version proceeds via peroxy isobutyric acid. 

Various pH aqueous solutions (pH = 1-6) of trifluoromethanesulfonic acid were prepared independently, and the model reaction of the silyl enol ether derived from cyclohexanone (2) with benzaldehyde was tested. Six independent experiments were performed (pH = 1, 2, 3, 4, 5, 6). In the pH 5 and 6 solutions, only a trace amount of the product was detected on TLC, the yields were less than 5%, and hydrolysis of 2 was also observed. In the pH 1-4 solutions, the silyl enol ether immediately hydrolyzed to give the original ketone, and no aldol adduct was obtained. From these experiments, the protons that may be produced from the hydrolysis of the lanthanide triflates were found not to be an active catalytic species in the present aldol reaction of silyl enol ethers with aldehydes the pH values of Yb(OTf)3 solutions were measured as 5.90(1.6x 10- M,THF-H20,4 l)and6.40(8.0x 10- M, HjO). 

Enol stannanes of cyclohexanone and propiophenone have been indicated to take part in r/treo-selective aldol reactions with benzaldehyde at low temperatures e.g. —78 °C), but to be erythro-seAsciiwe at higher temperatures ca 45 °C). Two complementary methods have been described for stereoselection in aldol-type reactions. Whilst a-mercurio-ketones show eryr/wo-selection in their reactions with aldehydes in the presence of boron trifluoride diethyl etherate, pre-formed lithium enolates and aldehydes, in the presence of simple trialkyl-boranes, lead to mixtures that are rich in the more stable threo-d do product. Aldol-type products arise from 1,3-alkyl migrations of alk-l-enyl alkyl acetals and ketals, in a reaction that is catalysed by boron trifluoride diethyl etherate (Scheme 52). Diastereoselection is possible, since (.E)-alkenyl acetals give the... 

Quantum mechanical calculations have predicted the transition state geometries for the reaction of cyclohexanone enamine with benzaldehyde [55]. Transition states involving the Re attack on the anti-enamine are lower in energy than the... 

A -Chloromethylamine attacks ketones in alkaline solution with formation of oxaziranes with cyclohexanone, compound 17 is produced in 50% yield. The reaction with aldehydes with zV-chloromethyl-amine yields predominantly acid amides. However, oxaziranes are also produced here as by-products. From benzaldehyde and A -chloro-methylamine, 2-raethyl-3-phenyloxazirane (15) was obtained in 10% yield. 

Optically pure (S)-benzyl methyl sulfoxide 139 can be converted to the corresponding a-lithio-derivative, which upon reaction with acetone gave a diastereomeric mixture (15 1) of the /S-hydroxysulfoxide 140. This addition reaction gave preferentially the product in which the configuration of the original carbanion is maintained. By this reaction, an optically active epoxy compound 142 was prepared from the cyclohexanone adduct 141181. Johnson and Schroeck188,189 succeeded in obtaining optically active styrene oxide by recrystallization of the condensation product of (+ )-(S)-n-butyl methyl sulfoxide 143 with benzaldehyde. 

This method fails, however, with bicyclic ketones such as 1-tetralones even in the presence of TsOH, affording only enol trimethylsilyl ethers such as 107 a [114, 115]. A subsequent investigation revealed that cyclohexanone reacts with equivalent amounts of N-trimethylsilyldimefhylamine 463 in the presence of TMSOTf 20 at -30 °C to give the enol silyl ether 107 a, whereas reaction of cyclohexanone, benzaldehyde, and chlorodimethyl ether with 463 and TMSOTf 20 or TCS 14 at 1-20 °C afforded the iminium salts 547, 548, and 549 in high yield [116-118]. Analogously, N-trimethylsilylpyrrolidine 550 and N-trimethylsilylmorphoHne 294 convert aldehydes such as benzaldehyde, at ambient temperature in the presence... 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

Transition-metal mediated carbene transfer from 205 to benzaldehyde generates carbonyl ylides 211 which are transformed into oxiranes 216 by 1,3-cyclization, into tetrahydrofurans 212, 213 or dihydrofurans 214 by [3 + 2] cycloaddition with electron-deficient alkenes or alkynes, and 1,3-dioxolanes 215 by [3 + 2] cycloaddition with excess carbonyl compound120 (equation 67). Related carbonyl ylide reactions have been performed with crotonaldehyde, acetone and cyclohexanone (equation 68). However, the ylide generated from cyclohexanone could not be trapped with dimethyl fumarate. Rather, the enol ether 217, probably formed by 1,4-proton shift in the ylide intermediate, was isolated in low yield120. In this respect, the carbene transfer reaction with 205 is not different from that with ethyl diazoacetate121, whereas a close analogy to diazomalonates is observed for the other carbonyl ylide reactions. 

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/r/c/ee. Alkyl chains of (40) make an organic microphase likely. 

Another class of substances of interest as bifunctional diazo components consists of special diamines that can be manufactured by the reaction of aromatic amines with benzaldehyde or cyclohexanone, e.g.,16 and 16a. 

In addition, the combination of KF and 1 H-crown-6 in the presence of BINAP-AgOTf, which was effective in accelerating the allylation reaction using allyltrimethoxysilane, could be used for the aldol reaction (Scheme 9.11).20 Thus, the reaction with the silyl enol ether derived from cyclohexanone and benzaldehyde in the... 

The diastereoselective aldol reaction of the tributyltin enolate of cyclohexanone with benzaldehyde in the presence of a catalytic amount of various metal triflates has been studied. The highest A-selectivity is observed with Pd(OTf)2, while Zn(OTf)2 in THF shows moderate yy -selectivity (Equation (68)).222 OSnBu3... 

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

The hydrophobicity-driven association of reactant molecules in aqueous solution has even been found in aldol reactions. The trimethylsilyl ether of cyclohexanone adds to benzaldehyde in aqueous solution at 20 °C in the absence of a catalyst to give aldol addition products with a synlanti stereoselectivity opposite to that of the acid-catalyzed reaction carried out in dichloromethane [746]. 

Houk next examined the aldol reaction of cyclohexanone with benzaldehyde (Reaction 6.20) and isobutyraldehyde (Reaction 6.21) with (6)-proline as the catalyst. Four diastereomeric TSs starting from the enamine formed from cyclohexanone and proline were optimized at B3LYP/6-31G for each reaction. These transitions states, 53 and 55, are shown in Fignre 6.23. In all of these TSs, proton transfer from the carboxylic acid group to the carbonyl oxygen accompanies the formation of the new C-C bond, creating a carboxylale and alcohol product. 

Julia [8,9] showed that methyl BT sulfone reacts with benzaldehyde in the presence of LDA under Barbier conditions to give styrene in 20% yield. Similarly, the methyl sulfone in the reaction 4-(t-butyl)-cyclohexanone provided the respective methyhdene derivative. 

As described above, zeolites can also act as solid base catalysts when the Si Al ratio is low and the extra framework cation is a large one such as The most basic common exchanged zeolite is CsX. With this material the aldol condensation of cyclooctanone with benzaldehyde gave only the monobenzylidene compound (Eqn. 10.23) 5 while reactions using piperidine, m nesium oxide or amorphous cesium aluminosilicate gave both the mono- and di-benzylidene products(Eqn. 10.12). The smaller ketones, cyclohexanone and... 

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