Cyclization cyclohexane synthesis

Gomez, A.M., L6pez, J.C., Fraser-Reid, B. (1994) Serial Radical Cyclization ofPyranose-Derived Dienes in the StereocontroUed Synthesis of Densely Functionalized Cyclohexanes. A Route to Woodward s Reserpine Precursor. Journal of Organic Chemistry, 59, 4048M 050. 

The allenylsilane ene reaction is also well suited for the synthesis of cyclohexane rings. Jin and Weinreb have described the process of Eq. 13.55 in a synthesis of 5,11-methanomorphanthridine, an Amaryllidaceae alkaloid [64], Conversion of aldehyde 163 to imine 164 with piperonylamine took place in situ. Heating the solution of imine at reflux in mesitylene for 2 h led to cyclization through the conformer shown. The yield of 165 from aldehyde 163 was 66%. 

In view of the ability of nitromethane to undergo a cyclizing bis-aminoalkylation when reacted with dialdehydes in the presence of amines 80,61) its application to other nitromethylene compounds seems an obvious extension. This reaction has already been verified when glutar-aldehyde is allowed to react with nitromethane and benzylamine in a 1 2 4 molar ratio in water, lr-methyl-l-nitro-2c,6c-bis-benzylamino-cyclohexane (110) is obtained in 56% yield 2) xhe same product is isolated in even higher yield (83%) on treatment of the nitroethane-glutaraldehyde cyclization product (6) with benzylamine However, further work is required to evaluate the preparative utility of this reaction principle for the synthesis of C-methyl branched triaminosugars. 

Lanthanide-catalyzed enyne cyclization/hydrosilylation was also applied to the synthesis of silylated alkylidene cyclohexane derivatives. For example, reaction of the 3-silyloxy-l,7-enyne 17 with methylphenylsilane catalyzed by Gp 2YMe(THF) at 50°G for 8h gave 18 in quantitative yield as a 4 1 mixture of trans cis isomers (Equation (11)). Employment of methylphenylsilane in place of phenylsilane was required to inhibit silylation of the initially formed yttrium alkenyl complex, prior to intramolecular carbometallation (see Scheme 8). 

Synthesis (Cavalla and White (Wyeth), 1969 1969 Bradley 1980 Kleemann et al. 1999) By condensation of 2-(m-methoxyphenyl)butyronitrile with ethyl 4-iodobutyrate by means of NaNH2 in liquid NH3 to give ethyl 5-cyano-5-(m-methoxyphenyl)heptanoate, which is cyclized by hydrogenation with H2 over Raney Ni in cyclohexane to yield 6-ethyl-6-(m-methoxyphenyl)hexahydro-2H-azepin-2-one this ketone is reduced with LiAIH4 in THF to 3-ethyl-3-(m-methoxyphenyl)hexahydro-IH-azepine, which in turn, is reductively methylated with HCHO, H2 and Pd/C in ethanol to give 1-methyl-3-ethyl-3-(m-methoxyphenyl)-hexahydro-1H-azepine, and finally demethylated by refluxing with 80% HBr to yield a racemic mixture of the final product. 

Further reactions that are highly suited to the synthesis of cyclohexane derivatives, such as cycloaddition processes, 1,3-dipolar additions, and Diels-Alder cyclizations, have been used extensively. In the latter set, carbohydrate-based dienes or dienophiles have been employed and, in addition, intramolecular processes have provided highly suitable means of synthesizing complex polycyclic systems. 

Increasingly, this process has been adapted to the synthesis of heterocyclic systems. One or both of the phenyl substituents in stilbene can be replaced by a heteroaromatic system, and some of the more important of these cyclizations are recorded in Table I. The formation of benz[A]isoquinoline by photolysis of 4-styrylpyridine in cyclohexane is accompanied by the formation of 1- and 3-cyclo-hexylbenz[A]isoquinoline.346... 

Michael addition followed by an aldol cyclization can be used for stereoselective synthesis of cyclohexanes. 

Several routes to cycloalkanes have been developed (Fig. 4). Bolton [29] described the synthesis of azabicyclo[4.3, 0]nonen-8-ones using an intramolecular Pauson-Khand cycliza-tion. The relative stereochemistry was controlled in this cyclization step which proceeded in good yield regardless of whether the nitrogen atom bore an allyl (shown) or propargyl (not shown) substituent. The ene reaction was employed in a route to trans-substituted cyclopentane and cyclohexanes [30], Reductive cleavage from the resin with LiBFL, provided the diol or, alternatively, cleavage with Ti(OEt)4 produced the diester. 

Two other examples of the synthesis of bicyclic compounds whose skeleton consists only of carbon atoms are shown in Sch. 24, each of them is instructive in its own way. Upon irradiation of the cyclohexane derivative 65, not the expected product from a hydrogen abstraction from the allylic position, but the bicyclo[3.3.1]heptane 67 was obtained by cyclization of the less stable biradical 66-B [57]. The reason for this is the exclusive hydrogen back-transfer of the more stable biradical and it underlines the importance of this process in regioselectivity phenomena of the Norrish-Yang reaction. 

Crystallography, of melezitose, II, 14 Cuto-cellulose, III, 187 Cyanohydrins, in synthesis of higher-C sugars, I, 1-36, 37, 38 Cyclization, of hexose derivatives, III, 53 Cycloamyloses, III, 254 305 V, 266 Cyclohexane, 1,3-diamino-2,4,5,6-tetra-hydroxy-. See Streptamine. 

The enaminones obtained by condensation of cyclohexane-1,3-diones with aminoace-taldehyde acetals can be cyclized with p-toluenesulphonic acid to 4-oxotetrahydroin-doles, which are useful synthons for synthesis of the corresponding carbolines40 (equation 25). 

A homoveratryl enaminone derived from cyclohexane-1,2-dione was cyclized through a 1,4-addition at the a,/ -unsaturated ketone moiety of the enaminone319 (equation 237). The spiro compound obtained, which is a useful intermediate in the synthesis of erythrina-alkaloids, demonstrates the special character of a-ketoenamines. 

Ring closure to cyclobutanes and cyclopentane-s The synthesis of cyclo-propanones by elimination of lithium thiophenoxicMe with this base has been extended to similar syntheses of functionalized cyclob tanes and cyclopentanes, as shown in equations (I) and (II), When extended to synthesis of a cyclohexane derivative, this method resulted in a very low yield. One possible mechanism is formation of a dianion followed by loss of thiophenoxid e ion to give a carbene-anion, which cyclizes with loss of the second thiophenoxide ion. 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

---