Cyclododecanone, synthesis from

A three-step synthesis starts from cyclododecanone. Reaction with chlorine gives 2-chlorocyclododecanone which is reacted with 2 mol of vinyl magnesium chloride to give 1,2-divinylcyclododecan-l-ol. This is finally converted into 5-cyclohexadecen-l-one by an oxy-Cope rearrangement [126] ... 

Dehydrations of dione (61) via the Paal-Knorr synthesis lead to heterophanes (58)-(60) (68TL2181, 69T5357). Dione (61) is readily prepared from cyclododecanone by conventional procedures (64E620). 

Radical ring expansion1 (14, 317-318). This reaction has been used for synthesis of muscone (3) from cyclododecanone. Alkylation of the ketone with 3-chloro-... 

This ring expansion has been applied to the synthesis of the 15-membered ( )-muscone [37], First cyclododecanone was tranformed to cyclotridec-3-enone (V/67) in a five step synthesis [38]. The latter, treated with the Grignard reagent formed from prop-l-enyl bromide, generated a mixture of the isomeric compounds, V/68, in nearly 50 % yield. Obviously the methyl group sterically... 

These reactions become more realistic if derivatives of a,/3-epoxy ketones are used. These can be easily prepared by oxidation of the corresponding a,/3-unsa-turated ketones with peracids or hydrogen peroxide (Scheme VIII/13). The driving force in studying this kind of reactions is the importance of the economic synthesis of the natural 15-membered ketones, muscone and cyclopentadeca-none, from cyclododecanone, an easy available and inexpensive starting material (Scheme VIII/14) [35] [36]. 

The transformation of cyclododecanone via IX/9 to the bicyclic intermediate, IX/10 is possible through an internal enamine reaction. Cleavage of the central ketone bridge gives the 14-membered product IX/11 [3]. This reaction was a key step in the synthesis of ( )-muscone (IX/15), Scheme IX/2, [4]. On treatment with base, the bicyclic intermediate, IX/13, prepared from 2-nitrocyclotri-decanone (IX/12), was quantitatively (R=H) [5] (or in 47 % yield (R=CH3) [4]) converted into the enlarged product IX/14. The retro aldol reaction was not... 

In the translactonization process the alcoholate acts as an internal leaving group from displacement by a side-chain alcohol. However, nucleophiles other than an alcohol may also displace. This can be a carbon atom in an a-position to a sulfone group as in IX/64 (Scheme IX/11) (various bases were used). The 15-membered IX/64 is isolated in 80 % yield. This synthesis represents a transformation of cyclododecanone via IX/63 to IX/66 to muscone [31]. 

The above conditions allow the synthesis of a large variety of a,a-dialkyl substituted ketones including spiro derivatives and cyclopentanones, cyclohexanones, cycloheptanones and cyclododecanones bearing two alkyl groups at die a-posidon (Scheme 162, e Scheme 165, c Scheme 166, e Scheme 186, a and b Scheme 187 Scheme 188, a Scheme 189, a and The reactions are less selective when the dichlorocarbene is generated from bromodichloromethane and lead to gem-dichlorocyclopropanes if the dichlorocarbene is produced from chloroform and potassium r-butoxide (Scheme 162, f Scheme 188, b Scheme 189, c). ... 

Eschenmoser, A., Eelix, D., Ohioff, G. New fragmentation reaction of a,P-unsaturated carbonyls. Synthesis of exaltone and rac-muscone from cyclododecanone. Helv. Chim. Acta 1967, 50, 708-713. 

Chlorocyclopentadec-2-enone 2 was obtained in 66% yield when the dichlorocarbene adduct 1 of 1-trimethylsiloxycyclotetradecene was stirred in the presence of dilute hydrochloric acid. This is the key step in a six-step synthesis of ( + )-muscone from cyclododecanone (36% overall yield). 

Concerning other reactions that make use of nitrous oxide as the oxidant, a process developed by BASF is worth mentioning, which involves the synthesis of cyclododecanone, a raw material for Nylon-12 and Nylon 6-12 [12]. Cyclodode-canone is oxidized to 1,12-dodecanedioic acid by oxidative cleavage with nitric acid. It is currently made by a five-step sequence from cyclododecatriene. The first step of the new process is the synthesis of cyclododecatriene from butadiene, which is then reacted with nitrous oxide, to produce cyclododecadienone, which is finally hydrogenated to cyclododecanone. The yield to cyclododecanone is significantly higher than with the conventional process, waste is reduced and investment costs are lower. BASF already has a contracted customer and is building a plant due to come on stream in 2009. 

Although in a recent paper (70) it was reported that the procedure has been improved to provide 55 in a yield as high as 2.6% starting from cyclododecanone through 12 steps, the claim of a novel synthesis of 55 involving acidic rearrangement of the cis precursors (71a) has proved to be erroneous (71b). 

One of the best examples for three-carbon ring expansion is the total synthesis of DL- and (/ )-muscone starting from a cyclododecanone derivative [5, 13], A good yield of ring expansion product is obtained by the use of selenide as the radical precursor (Scheme 8). 

One of the first industrial muscone syntheses stems from work at BASF. [182] Analogous to the synthesis of exaltone, cyclododecanone is converted, by reaction with but-3-yn-2-ol, into a diol, which is further transformed by a Meyer-Schuster rearrangement and Nazarov cyclisation into a methyl-substituted bicycle. A very short route to the same product was described by Mitsui Petrochemical Industries a few years later this involved the direct conversion of cy-clododecene with crotonic acid in the presence of polyphosphoric acid, and resulted in a remarkable yield of 54 %. [183]... 

Cyclododecanone, which became the most accessible of medium-ring ketones following Wilke s discovery of the butadiene-cyclotrimerization process, is an important starting point for manufacture of the valuable musk ketones. Two syntheses of muscone, commencing from cyclododecanone are outlined below. The first synthesis, which emanated jointly from Eshenmoser s group in Zurich and laboratories of the Swiss perfume firm, Firmenich Cie., illustrates a three-carbon ring expansion reaction based on the widely applicable tosylhydrazone version of the oxidoketone— alkynone fragmentation. ... 

Another synthesis of J/-muscone, commencing from cyclododecanone, is based on application of Gutsche s photoiytic method for the cieavage of key bicycloketone (A) to methyl 3-methylcyclopentadecanecarboxylate (B). 

---