Cyclohexanone, annelation

Ethoxyallylidenetriphenylphosphorane (94) has been shown to be a novel cyclohexanone annelating reagent, undergoing addition to a/8-unsaturated ketones to produce 2-alkoxycyclohexa-1,3-dienes (masked cyclohexenones and useful eno-philes) (Scheme 24)7 The method is highly versatile, permitting the construction of monocyclic, fused, bicyclic, and spiro-ring systems. 

Cyclohexanol, 1-methyl-, 53, 94 Cyclohexanone, 54, 40 annelation to, 53, 75 CYCLOHEXANONE, 2-DIAZ0-, 51, 86 Cyclohexanone, 2-(3-ethyl-5-methyl-4-isoxazolylmethyl)-, 53, 72... 

Problem 17.49 The Robinson annelation reaction for synthesizing fused rings uses Michael addition followed by intramolecular aldol condensation. Illustrate with cyclohexanone and methyl vinyl ketone, CHj=CHCOCH,. <... 

The isoxazole annelation reaction2,3 is a general method for fusing a new cyclohexanone ring onto an existing system and is complementary to the well-known Robinson annelation.4 It has several major advantages ... 

Salicylate annelatiun.1 A new method involves conversion of a cyclohexanone llllo the annelated 3-carbomethoxy-2-pyrone by reaction of the enolate with dimethyl iliclhoxyincthylcnemalonate2 to form a 3-carbomethoxy-2-pyrone. This product undergoes a facile Diels-Alder reaction with 1,1-dimethoxyethylene with loss of C02 anil ( II, OII to give a salicylate... 

Phenol annelation.1 This modified methyl vinyl ketone can be used for synthesis of 5,6,7,8-tetrahydro-2-naphthol or 5-indanol by reaction with the lithium enolate of cyclohexanone or cyclopentanone, respectively. The former reaction is formulated in equation (I). 

Cyclopentenone annelation. A typi cal example for use of 1 for synthesis of cyclopentenones is illustrated for annelat ion of cyclohexanone (equation I). 

Robinson annelation. The Robinson annelation of unactivated cyclohexanones with t/ ans -3-pentene-2-one under usual conditions proceeds in low yield, if at all. However, Scanio and Starrett report that the sodium enolate of 2-methylcyclohexa-none (1) in dioxane reacts with 1 eq. of /rom-3-pentene-2-one (2) to give fw-4,10-dimcthyl-l(9)-octalone-2 (3) in 65% yield. If DMSO is used in place of dioxane, the... 

Robinson annellation reaction. Formation of six-membered-ring ,(i-iinsaturatcd ketones by condensation of cyclohexanones with methyl vinyl ketone or its equivalents, followed by an intramolecular aldol condensation. 

The same strategy, but with the opposite polarity, along with other enone approaches is illustrated by the bicyclic enone 84 needed for the synthesis of the terpene cadinene. Aldol disconnection gives the 1,5-diketone 85 which we expect to make by a Michael addition.18 Hence we require a specific enol equivalent of cyclohexanone to add to the enone 86, and we have rediscovered the Robinson annelation.19... 

When an oc,/)-unsaturated ketone is the acceptor, subsequent ring closure to yield a six-membered ring can occur, in two modes. As shown in Scheme 3, the initially formed enolate oxygen can add to the immonium ion of the dipolar intermediate to generate a dihydropyran (e.g., 3.2, Y = 0, X = C). Alternatively, proton transfer from the initially formed enolate and subsequent carbon-carbon bond construction between the enolate and the immonium ion can produce a new cyclohexanone ring. Elimination of the amine usually ensues to generate the corresponding cyclohexenone. This amine-promoted Robinson annelation is commonly referred to as a Stork annelation (3, 22). 

Robinson annelation. Robinson annelation of substituted cyclohexanones with the reagent offers an entry into eremophilone-type sesquiterpenes. Thus the total synthesis of ( )-nootkatone (2) has been achieved by the annelation of (1) with frans-3-pentene-2-one in the presence of sodium hydride.3 In this case only one isomer was isolated. However, Coates and Shaw4 noted that the steric outcome of... 

Dibenzofulvene (100), which is a byproduct of fluorenylmethoxycarbonyl (FMOC) deprotection in peptide synthesis, undergoes Michael addition reactions with carbanions. Conversion of 100 with the silyl enol ether of cyclohexanone (101) and a desilylation reagent furnishes directly the ketone 102, that now can be subjected to the already described acid mediated intramolecular cyclodehydration procedure followed by aromatization. The product is again a polycyclic fluoranthene (103), that can be considered as a naphtho annelated fluor-ene in this sequence (see Scheme 50 [150]). 

Scheme 51. General annelation procedure using enamine derivatives of cyclohexanone [151] a) dioxane, 18 h, reflux b) CH3S03H c) 10% Pd/C, triglyme, reflux...

Besides the ene oxide and the silyl enol ether discussed above the enamine derivatives of cyclohexanone can be used as a cyclohexanone equivalent as well in these novel annelation procedures [151]. Alkylation of the enamine 108 with l,5-bis(2 -bromoethyl)naphthalene (109) afforded the expected diketone 110 in 80% yield (see Scheme 51). Cyclodehydration of 110 with methanesulfonic acid... 

Chloro-2-(diethoxyphosphoryl)oxy-l-propene (64) is used by Welch in a one-pot annelation of cyclohexanone to provide 66.39 Chloropropenylphophonate (64) is prepared from l,3-dichloroacetone and trimethyl phosphite.39... 

Annelation of unsymmetrically substituted cyclohexanones. Stotter and HiU examined this reagent for a method of position-specific annelation of unsymmetrically substituted cyclohexanones, which can be converted specifically into either of the two possible lithium enolates (3, 310-311 4, 299). They reasoned that an allylic iodide should react rapidly before equilibration of the enolate can occur and that the carboxylate substituent on the double bond should suppress 1,4-elimination of hydrogen iodide and also aid in the isolation of the alkylated ketone. These expectations were realized. Thus annelation of the lithium enolate (2) with (1) at 0° followed by hydrolysis gave the acid... 

Bis-annelations. Danishefsky et al. have shown that this reagent can be used to effect bis-annelation. The product of addition of (1) to an enamine of a ketone, for example cyclohexanone, gives, after ketalization, the product (2). 

Annelation. This reagent reacts slowly, but in high yield, with cyclohexanone and cyclopentanone to form a tertiary alcohol. The annelation of cyclohexanone to form A -octalone is illustrated (equation I). This annelation differs from a Robinson annelation in that the 3-ketobutyl group is introduced at the site of the carbonyl group rather than in the a-position. ... 

The Robinson annelation was introduced in Chapter 26, p. 638. The flattened chair conformation of cyclohexanones shown here is described in detail in Chapter 32, p. 830. 

A further report has appeared on the use of j8-vinyl-butenolide in lactone annelation by condensation with jS-keto-esters, in this case 2-ethoxycarbonyl-cyclohexanones. Although yields of the desired products (58) are only moderate, the method clearly has considerable potential. 

All of these disconnections describe annulation (annelation) routes to cyclohexanone derivatives. There are tactical issues involved with executing the strategies in the lab that we will not discuss here. Of course these are not the only ways to construct simple cyclohexanone derivatives. The problems explore several other approaches. Nonetheless these are versatile strategies that have been widely used in organic synthesis. One point to take away from this exercise is that 6-membered rings can be prepared without resorting to use of A-functions. Although we have seen this only for carbocycles, it turns out this is true for heterocycles as well (see the problems). 

Tetrahydropyridoimidazolin-2-ylidene-containing complex 80 was evaluated for TH of acetophenone and cyclohexanone in KOH/i-PrOH (Figure 13.8). Cationic Rh complexes 81 with pyridazine annelated bis-NHC ligands showed a good catalytic activity even for sterically hindered ketones in refluxing KOt-Bu/i-PrOH. Activities at room temperature up to 97% conversion could be obtained after 48 h for the TH of acetophenone. 

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