Cyclohexane-1,2-diones, synthesis

Within the cubane synthesis the initially produced cyclobutadiene moiety (see p. 329) is only stable as an iron(O) complex (M. Avram, 1964 G.F. Emerson, 1965 M.P. Cava, 1967). When this complex is destroyed by oxidation with cerium(lV) in the presence of a dienophilic quinone derivative, the cycloaddition takes place immediately. Irradiation leads to a further cyclobutane ring closure. The cubane synthesis also exemplifies another general approach to cyclobutane derivatives. This starts with cyclopentanone or cyclohexane-dione derivatives which are brominated and treated with strong base. A Favorskii rearrangement then leads to ring contraction (J.C. Barborak, 1966). 

Nair and co-workers reported the diastereoselective synthesis of spiro y-butyro-lactones from 1,2-dicarbonyls [125]. The authors studied the reaction with 1,2-cyclohexane dione 230 which produces the desired lactone 232 in good yields Eq. 22a. Isatins 233 are more reactive, but the products 235 are obtained as a 1 1 separable mixture of diastereomers Eq. 22b. The Nair research group extended this methodology to include homoenolate addition to tropanone 236 to form bicyclic 5-lactones 238 Eq. 22c [126]. 

Sheng and co-workers [113] described an efficient Hantzsch reaction for the synthesis of polyhydroquinolines 67 applying a solvent-free microwave-assisted one-pot four-component reaction of PEG-bound acetoacetate, 1,3-cyclohexane-dione, an aromatic aldehyde and ammonium acetate in the presence of a catalytic amount of PPA. The target compounds 67 were obtained in excellent yields and purities, after cleavage from the PEG support using NaOEt in EtOH. The reactions were carried out in domestic microwave oven (Scheme 51). 

The so-calSed Wieland-Miescher ketone is a valuable starting material used in the synthesis of steroid hormones. How might you prepare it from 1,3-cyclohexane-dione ... 

An attempt to prepare reduced S-quinolinones from cyclohexane-1,3-diones (or their tautomers) and 3-amino-2-metbyiacrolein gave 1,8-acridinediones with the loss of one carbon atom (a mechanism for this reaction has been suggested). The acridinediones were also synthesized (in 40-79% yield) from the cyclohexane-diones, propanal and ammonium acetate. Further investigation of the former synthesis showed that quinolinones are also produced in the reaction but as they are oils, they had to be isolated as their salts (see also Chapter 53). 

A similar approach has been used for the synthesis of 3-lH-pyrazolo[3,4-fc]pyridyl-indole ° and 2-aminochromene libraries, the latter being performed solvent free using a clay as a support and base. In addition, a library of over 100 derivatized substituted 2-pyridones (21 x 5 members) has been prepared by the reaction of 1,3-cyclohexane-diones, dimethylformamide dimethylacetal, and various cyanoacetamides (Scheme 4.10). The outcome of the reaction could be controlled to furnish different products by changing the basicity of the medium to involve either the amide or nitrile functionality of the cyanoacetamide substrate during the 2-pyridone ring-formation step. 

Another route to the synthesis of steroids by the scheme under consideration was developed by Wilds and his colleagues [57, 604, 641-643] (Scheme 60). The successive addition of rings B and A to 1,3-cyclohexane-dione (40) by the use of Robinson s method of ring formation twice led via... 

Several substituted cyclohexane derivatives may also be obtained by the reduction of a benzenoid precursor. Partial reduction of resorcinol, for example, and subsequent methyla-tion yields 2-methylcyclohexane-I,3-dione, which is frequently used in steroid synthesis (M.S. Newman, 1960 see also p. 71f.), From lithium-ammonia reduction of alkoxybenzenes l-alkoxy-l,4-cyclohexadienes are obtained (E.J. Corey, 1968 D). 

A second class of herbicides primarily affects ( -carotene desaturase. These herbicides are apparent feedback inhibitors of PD as well. This class of compounds includes dihydropyrones like LS 80707 [90936-96-2] (56) and 6-methylpyridines (57,58). The third class consists of the ben2oylcyclohexane-diones, eg, 2-(4-chloro-2-nitroben2oyl)-5,5-dimethyl-cyclohexane-I,3-dione. This class of atypical bleaching herbicides induces phytoene accumulation when appHed either pre- or post-emergence. However, it does not inhibit phytoene desaturase activity in vitro (59). Amitrole also has been considered a bleaching herbicide, though its main mode of action is inhibition of amino acid synthesis. 

The more traditional methods of phenazine synthesis falling into the type A synthesis are altogether less satisfactory than the application of the Beirut reaction. Traditionally, Ris prepared phenazine in low yield by heating o-phenylenediamine and catechol in a sealed tube at 200 °C (1886CB2206) however, the method appears to be unsatisfactory at best and gives, in addition to phenazine, 5,10-dihydrophenazine in varying amounts (Scheme 53). Several variants of this procedure exist o-benzoquinone has been used in condensation with 0-phenylenediamine and yields as high as 35% have been reported, and 1,2,3,4-tetrahydrophenazine has been prepared by condensation of o-phenylenediamine with cyclohexane- 1,2-dione. 

The authors developed two general concepts for the synthesis of these mono-disperse, defined oligomers. The oligomers can be built up in a stepwise fashion, e.g. via addition of organomelallic species to cyclohexane-1,4-dione followed by aromatization to the oligo(arylene) (e.g. for 25). 

Because free or esterified imidazole(4,5)-acetates 745 are currently accessible only via a rather tedious multistep synthesis via (4,5)hydroxymethylimidazole [224— 226], it seemed obvious to react amidines such as isobutyraminidine-HCl 742 with commercially available methyl or ethyl 4-chloroacetoacetates 743a, b to obtain 745 directly in one step. Because of the low reactivity of the 4-chlorine in 743, however, reaction of 743, e.g. with isobutyramidine-HCl 742 in the presence of sodium methylate in methanol, affords exclusively 2-isopropyl-6-chloromethyl-pyri-midin-4-one 744 [227], whereas treatment of 743b with NaOEt in EtOH gives, in the absence of amidines, 2,5-bis(ethoxycarbonyl)cyclohexane-l,4-dione in nearly quantitative yield [228, 229]. 

In a detailed investigation, Turner and coworkers have described the preparation and application of solid-supported cyclohexane-1,3-dione as a so-called capture and release reagent for amide synthesis, as well as its use as a novel scavenger resin [125]. Their report included a three-step synthesis of polymer-bound cyclohexane-1,3-dione (CHD resin, Scheme 7.104) from inexpensive and readily available starting materials. The key step in this reaction was microwave-assisted complete hydrolysis of 3-methoxy-cyclohexen-l-one resin to the desired CHD resin. 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

When an a-chloroaldehyde or an a-chloroketone is condensed with a /3-ketoester, in the presence of aqueous base, a furan is produced bearing an ester substituent at the /3-position. It is thought that the reaction is of the aldol type intermediate dihydrofurans (256) have been isolated in certain cases (Scheme 70) (74BSF519). The condensation of ethyl bromopyru-vate and sodium oxaloacetate follows a similar mechanism (54JOC1671). The one-pot synthesis of 2,4,5-trisubstituted furans (257) from ketones and ethyl 3,4-dibromo-2-butenoate is a useful addition to a well known route (80S52). The analogous reaction of cyclic /3-diketones, i.e. cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-l,3-dione, results in the formation of the condensed furans (258) and (259). These reactions are preformed either in ethanol with sodium ethoxide or in DMF with potassium carbonate. 

The reaction of 1,2-dicarbonyl compounds with amidrazones, semicarbazide, thiosemicarbazide and aminoguanidine has also been used for the synthesis of condensed 1,2,4-triazines. Cyclohexane-, cycloheptane- and cyclooctane-1,2-diones (489) with amidrazones (453) afford the cycloalkatriazines (490) (78HC(33)189, p.66l). 

A nitrile-stabilized carbanion is also involved in a synthesis of a fused pyranone system (81S225). A range of 2-ureidomethylenecyclohexane-l,3-diones, e.g. (308), react with activated acetonitriles in the presence of a strongly basic catalyst to produce 5-oxo-5,6,7,8-tetrahydrocoumarins (309). Since the substrates are readily available from cyclohexane-1,3-diones by reaction with triethyl orthoformate and a urea, the synthesis is attractive (Scheme 88). Furthermore, it has been applied to a pyran-2,4-dione, whereupon the 2,5-dioxopyrano[4,3-6]pyran (310) is formed. 

Humphrey, C.E., Easson, M.A.M., Tierney, J.P. and Turner, N.J., Solid-supported cyclohexane-1,3-dione (CHD) a capture and release reagent for the synthesis of amides and novel scavenger resin, Org. Lett., 2003,... 

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