Cyclohexanones 4,4-disubstituted

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

It would be pertinent to point out (25,27) that the trisubstituted isomer of the enamine of 2-aIkylcyclohexanone reacts in a quantitative manner with ethyl azodicarboxylate to give the addition product (35). This reaction in Conjunction with NMR spectroscopy can thus be employed for the determination of the amount of the trisubstituted isomer. According to the authors, hydrolysis of 35 furnishes the corresponding cw-2,6-disubstituted cyclohexanone (36) this seems unlikely since it would involve the stereo-electronically unfavored equatorial protonation of the enamine. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

In the reactions of arylsulfenyl chlorides with enamines one encounters an unusual result for enamine chemistry, in that the formation of 2,6-disubstituted cyclohexanone enamines predominates over the formation of monosubstitution products 474). A rationalization of this result suggests the formation of an intermediate which can act as an intramolecular electrophile in formation of the second carbon-sulfur bond. 

Tetrahydroquinazolines are more conveniently classified as 4,5-tetramethylene pyrimidines and their reactions are accordingly typical of pyrimidines. 2,4-Disubstituted derivatives have been prepared by condensation of 1-ethoxycarbonyl cyclohexanones with ureas and thioureas (Scheme 9). For monosubstituted derivatives the... 

A diastereoselective route to d.v-2,3-disubstituted cyclohexanones is based on the kinetically controlled protonation of the enolate obtained via the addition of an arylacetonitrile to 2-sub-stituted 2-cycloalkenones in THF or in THF/HMPA mixtures at — 70-0 °C 299,30°, see also refs 301, 302 and 403. 

Owing to the predominance of the less-substituted enamine, alkylations occur primarily at the less-substituted a-carbon. Synthetic advantage can be taken of this selectivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from C-alkylation are hydrolyzed in the workup procedure. 

The superscript e refers to the equatorial position of a substituent (here Br) in that ring of the adamantane which is disubstituted (here the cyclohexanone ring C(l,2,3,4,5,9)]. A superscript "a denotes the corresponding axial position. 

The regio- and diastereo-selectivity of the Michael addition of 2-phenylcyclo-hexanone with a,p-unsaturated ketones are dependent on the reaction conditions. Mixtures of all six diastereoisomers resulting from reaction at either the 2- or 6-position of the cyclohexanone ring can be obtained using solid potassium hydroxide with tetra-n-butylammonium or A-benzylephcdrinium bromide catalysts. At 20°C with tetra-n-butylammonium bromide, the ratio of the 2,2- and 2,6-disubstituted cyclohexanones is ca. 3 2, but at higher temperatures with solid potassium f-butoxide the kinetically formed 2,6-isomer predominates (ca. 5 1) with the (2S,6R, R )-stereoisomer dominant, whereas greater amounts of the thermodynamically preferred 2,2-(2S,lR )-isomer are obtained with the chiral catalyst [61]. 

Allan, G., Camell, A.J., Escudero Hernandez, M.L. and Pettman, A., Desymmetrisation of 4,4-disubstituted cyclohexanones by enzyme-catalysed resolution of their enol acetates. J. Chem. Soc. Perkin Trans. 1, 2000, 3382. 

The first asymmetric procedure consists of the addition of R2Zn to a mixture of aldehyde and enone in the presence of the chiral copper catalyst (Scheme 7.14) [38, 52]. For instance, the tandem addition of Me2Zn and propanal to 2-cyclohexenone in the presence of 1.2 mol% chiral catalyst (S, R, R)-1S gave, after oxidation of the alcohol 51, the diketone 52 in 81% yield and with an ee of 97%. The formation of erythro and threo isomers is due to poor stereocontrol in the aldol step. A variety of trans-2,3-disubstituted cyclohexanones are obtained in this regioselective and enantioselective three-component organozinc reagent coupling. 

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

The role of the metal catalyst in the hydrogenation reaction and its stereoselectivity has been widely studied (9). Group Vtll metals are generally used, but different behaviours are observed. In the hydrogenation of disubstituted phenols palladium mainly gives cyclohexanone derivatives, rhodium and platinum are very selective for the c/5 isomer, whereas nickel is more selecive for the tra/ 5 isomer (9). 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

The creation of all-carbon quaternary chiral centers by asymmetric conjugate addition is a challenging task. A chiral heterocyclic carbene 199 has been used as a ligand for this reaction. Chiral 3,3-disubstituted cyclohexanones 200 were obtained by this method with up to 85% ee (equation 126) . ... 

Application of the method described above to unsymmetrical cyclic ketones such as 2-substituted cyclohexanones gave 2,7-disubstituted and 2,2,7-trisubstituted cycloheptanones (Scheme 8). Treatment of a-sulfinyl lithium carbanion of 1-chloroethyl p-tolyl sulfoxide with 2-substituted cyclohexanones (210a and 210b) afforded adducts as a mixture of two diastereomers. The main adducts were first treated with f-BuMgCl followed by i-PrMgCl (4 equiv) at 0°C to room temperature to give the magnesium /3-oxido carbenoid 211. The... 

Cyclohexanones have been employed in reactions with thioureas to give quinazolines with varying degrees of saturation. For example, octahydroquinazolinedithiones (182) have been prepared from cyclohexanone and symmetrical313 315 or unsymmetrical314 disubstituted... 

Disubstituted cyclohexanones (325 equation 73) are easily prepared by a double Michael process, in which the intramolecular addition forms the six-membered ring.77 Either the cis or trans compound... 

Wipf has shown that 4,4-disubstituted cyclohexanones undergo nucleophilic attack where the facial selectivity is determined by dipolar control. Thus, compounds of the type 23 underwent nucleophilic attack anti to the electronegative substituent at C(4), whereas the fluorinated analogue, 24, underwent attack syn to the oxygen, in accordance with the inversion of the dipole moment. They found that the logarithm of the experimentally observed facial selectivity for nucleophilic attack was correlated linearly (R = 0.998) with the calculated dipole moments. The facial selectivities were also shown to depend upon the nature of the nucleophile, hydride ions and alkynyl carbanions being essentially unselective. 

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). 

Pyrimidine derivatives are frequently used as functional materials or are found in their partial structures. A great number of methods for construction of pyrimidine skeleton have been reported in which the majority is the condensation of a C - C - C unit (e.g., malonaldehyde, malononitrile, diethyl malonate) and an N-C-N unit (e.g., urea, guanidine) [46]. On the other hand, the general method involving a combination ofC-N-C, C-C and N units is not known to our best of knowledge. Thus, the present TCRT will be an alternative method for the preparation of 4,5-disubstituted pyrimidines, however, this reaction suffers from limited scope of ketones. When cyclohexanone is employed, tetrahydroquinazoline 26d is effectively formed... 

Previously, Ireland-Claisen ester-enolate rearrangement of the corresponding a-propionyloxy-allylsilane led to model system 5.44 Therefore, elaboration to 4 via rearrangement of 15 was pursued. To complete our retrosynthetic analysis, a plausible route to 15 was devised, involving straightforward homologation of 2P,3a-disubstituted cyclohexanone 17 to cyclohexene-carboxaldehyde 16, which in turn undergoes silylanion addition and subsequent acylation (Eq. 8). 

An important modification is reaction of p-dicarbonyl compounds with [hydrox y(tosyloxy)iodo]benzene and selenourea as a one-pot synthesis [177], Similarly, a-tosyloxylation of acetophenones, cyclohexanone, or pentan-3-one with the same reagent, followed by treatment with arylselenobenzamides, gives 2,4-disubstituted and 2,4,5-trisubstituted 1,3-selenazoles [178],... 

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