Cyclohexanones intramolecular alkylation

A pseudo 1,2 cycloaddition (actually a 1,3 cycloaddition, but may be considered a 1,2 type if a three-membered ring is considered analogous to an alkene) is observed when the pyrrolidine enamine of cyclohexanone is allowed to react with N-carbethoxyaziridine (129) to produce octahydro-indole 130 91). Octahydroindoles and pyrrolidines can also be produced through the intramolecular alkylation of the enamines of certain halo-ketourethanes 176a). 

Intramolecular alkylation, although it is enticing, has not been developed as a method for cyclohexanone construction. Joseph P.A. Harrity of the University of Sheffield reports (J. Org. Chem. 68 4392, 2003) that TiCl smoothly transforms the enol ether 10, prepared from the corresponding alkynyl phosphonium salt, into the 2-aryl cyclohexanone 11. Alkynyl ethers such as 10 are readily prepared in enantiomerically-enriched form. Would the enantiomeric excess be maintained on cyclization ... 

Delivery of an electrophile to the less hindered face of an enolate also occurs in intramolecular alkylation reactions. When 500 was treated with potassium fert-butoxide, a mixture of (E) and (Z) enolates (501 and 502. respectively) was obtained. Intramolecular displacement of bromide generated a single isomer (503). In this case, the electrophile can approach the enolate from only one face (the bottom or a face). Because of this conformational constraint, both (E) and (Z) enolates lead to the same product. In cyclopentanone and cyclohexanone enolates. an increase in the size of a facial blocking group increases selectivity. When that group was small, the selectivity decreased. 

First, cyclohexanone is alkylated by 32 giving rise to the masked triketone 33. On catalytic hydrogenation of 33, the isoxazole ring is reductively opened to give the enaminone 34, which cyclizes in situ to the enamine 35. On treatment with aqueous NaOH, 34 is converted to the 1,5-dione 36 (by enamine hydrolysis and acid cleavage of the 1,3-dicarbonyl system of the triketone intermediate), which undergoes base-induced intramolecular aldol condensation to the bicycloenone 37 (in analogy to a Robinson annulation) [317] ... 

Intramolecular alkylation of w-bromo-enolates is a useful synthetic route to substituted cyclohexanones (Scheme 15) with some limitations it is also applicable to the synthesis of cycloheptanone derivatives. ... 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /2-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-/2 proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, N02), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,/ -unsaturated... 

Treatment of 5,6-unsaturated sugar 382 (Scheme 11.79) with mercury(ll) salts was shown to induce what is called the second Ferrier rearrangement. The reaction proceeds via mercuration of the double bond and, in the presence of water, the alkyl glycoside 383 is then hydrolyzed to the aldehyde 384, which undergoes intramolecular aldol reaction to produce a (3-hydroxy cyclohexanone 385. This reaction produces only six-membered rings. An excellent review by Ferrier and Middleton was pubhshed some years ago [300]. 

Synthesis by Other Cyclizations. The epimeric amines (49) have been made by means of a novel S 2 reaction of the corresponding 2-bromo-6-amino-cyclohexanone derivative. Double Michael addition of (+)-a-methylbenzyl-amine to cyclo-octa-2,7-dienone derivatives forms the basis of a synthesis of the enantiomeric forms of adaline (50). Intramolecular Friedel-Crafts alkylation has been used in the synthesis of derivatives of the 2,6-methanobenz-azepine, 2,6-methano-3-benzazocine, 2,6-methano-3-benzazonine, and... 

A popular and useful application of the conjugate addition reaction is the combined conjugate addition-intramolecular aldol strategy, commonly known as the Robinson annulation. When the Michael donor is a ketone and the Michael acceptor an a,p-unsaturated ketone, the product is a 1,5-diketone which can readily undergo cyclization to a six-membered ring. Typical Michael donor substrates are 2-substituted cyclohexanones, which condense with alkyl vinyl ketones to give the intermediate conjugate addition products 42 (1.52). The subsequent intramolecular... 

In 2004 List and Vignola proposed the use of 7a to tackle the challenging asymmetric a-alkylation of aliphatic aldehydes. The transformation itself is complicated by the possibility of many side reactions, among which are self-aldolisation and N-alkylation of the amine catalyst, producing a cataly-tically inactive tertiary ammonium salt. Thus, when the proline-catalysed reaction between cyclohexanone or propanal and benzylbromide was tested, only the products of proline benzylation were identified. Luckily, the intramolecular a-allg lation worked successfully and after a screening of several proline derivatives and different amines, 7a was identified as the catalyst of choice (Scheme 11.6). Bromides and iodides may be used efficiently in these reactions, whereas tosylates gave particularly slow reactions. 

The cyclic 8-keto ester produced in an intramolecular Claisen cychzation can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 17.5). Alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate, for instance, yields a 2-alkylcyclohexanone. The overall sequence of (1) intramolecular Claisen cyclization, (2) 8-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2, it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter... 

Scheme 7.4 Regiochemical possibilities for the intramolecular Schmidt reaction of a 2-alkylated cyclohexanone...

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